BioPAX pathway converted from "Diseases of metabolism" in the Reactome database. Diseases of metabolism Diseases of metabolism Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. Mutations that disrupt these processes by inactivating a required enzyme or regulatory protein, or more rarely by changing its specificity can lead to severe diseases. Metabolic diseases annotated here involve aspects of carbohydrate, glycosylation, amino acid (phenylketonuria), surfactant and vitamin metabolism, and biological oxidations. One somatic mutation that affects cytosolic isocitrate metabolism, often found in glioblastomas and some lymphoid neoplasms, is also annotated. Also described are mutated forms of adrenocorticotropic hormone (ACTH) that can lead to obesity, resulting in excessive accumulation of body fat. Diseases of carbohydrate metabolism Diseases of carbohydrate metabolism The processes by which dietary carbohydrate is digested to monosaccharides and these are taken up from the gut lumen into cells where they are oxidized to yield energy or consumed in biosynthetic processes are a central part of human metabolism and defects in them can lead to serious disease. Defects annotated here affect saccharide digestion in the gut lumen, fructose metabolism, and the pentose phosphate pathway. In addition, the defect in glucuronate catabolism that leads to essential pentosuria, a benign phenotype that is one of Garrod's original four inborn errors of metabolism, is annotated. Mucopolysaccharidoses Mucopolysaccharidoses The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders caused by deficiencies of enzymes catalyzing the stepwise degradation of glycosaminoglycans (GAGs, originally called mucopolysaccharides) (Neufeld & Muenzer in Scriver et al. 2001). Catabolism of the GAGs dermatan sulfate, heparan sulfate, heparin, keratan sulfate, chondroitin sulfate or hyaluronan may be blocked at one or more steps, resulting in lysosomal accumulation of GAG fragments of varying size. Over time these collect in the cells, blood and connective tissues ultimately resulting in progressive irreversible cellular damage which affects appearance, physical abilities, organ and system function, vision, and usually mental development (Lehman et al. 2011, Ashworth et al. 2006). Life expectancy is also reduced. There are 11 known enzyme deficiencies that give rise to 7 distinct MPS. These disorders are biochemically characterized by elevated levels of partially or undegraded GAGs in lysosomes, blood, urine and cerebro-spinal fluid (Muenzer 2011, Coutinho et al. 2012). The MPS are part of the lysosomal storage disease family, a group of about 50 genetic disorders caused by deficient lysosomal proteins (Ballabio & Gieselmann 2009). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Edited: Jassal, B, 2012-04-26 MPS I - Hurler syndrome MPS I - Hurler syndrome Mucopolysaccharidosis type I (MPS I, Hurler syndrome, Hurler's disease, gargoylism, Scheie, Hirler-Scheie syndrome; MIM:607014, 607015 and 607016) is an autosomal recessive genetic disorder where there is a deficiency of alpha-L iduronidase (IDUA, MIM:252800), a glycosidase that removes non-reducing terminal alpha-L-iduronide residues during the lysosomal degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate (McKusick 1959). In 1992, Scott and colleagues were able to clone and purify the gene that encodes this enzyme, IDUA, demonstrating that it spans approximately 19 kb and contains 14 exons (Scott et al. 1992).<br>Hurler syndrome is named after a German paediatrician Gertrud Hurler (1919, no reference available). The result is build up of heparan sulfate and dermatan sulfate in the body and increased urinary excretion of these GAGs. Symptoms and signs include hepatosplenomegaly, dwarfism, unique facial features, corneal clouding, retinopathy, progressive mental retardation appears during childhood and early death can occur due to organ damage (Campos & Monaga 2012). MPS I is divided into three subtypes, ranging from severe to mild phenotypes; Mucopolysaccharidosis type IH (MPSIH, Hurler syndrome, MIM:607014), mucopolysaccharidosis type IH/S (MPSIH/S, HurlerScheie syndrome, MIM: 607015) and mucopolysaccharidosis type IS (MPSIS, Scheie syndrome, MIM: 607016) respectively (McKusick 1972). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Edited: Jassal, B, 2012-04-26 3.2.1.76 Defective IDUA does not hydrolyse Heparan sulfate chain(6) Defective IDUA does not hydrolyse Heparan sulfate chain(6) Absence of alpha-L-iduronidase (IDUA, MIM:252800), the enzyme responsible for the removal of non-reducing terminal alpha-L-iduronide (Lido) residues during the lysosomal degradation of heparan sulphate (HS) and dermatan sulfate (DS) is the cause of MPS I disorders (MIM:607014). The nonsense mutations, W402X and Q70X and the rarer P553R account for approximately 50% of all MPS I alleles in patients with predominantly European origins (Scott et al. 1992, Bunge et al. 1994, Scott et al. 1992b). There are, however, considerable differences in the frequency of these mutations in patients from Norway and Finland when compared with other Eurpoean countries. In Scandinavia, W402X and Q70X account for 17% and 62% of the MPSI alleles, respectively, while in the other European countries W402X is about 2.5 times more frequent (48%) than Q70X (19%). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-04-26 Reactome DB_ID: 2090055 1 lysosomal lumen GO 0043202 beta-D-IdoA-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63809] beta-D-IdoA-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group Reactome http://www.reactome.org ChEBI 63809 Reactome DB_ID: 1605715 1 water [ChEBI:15377] water ChEBI 15377 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2207701 IDUA mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity IDUA P553R [lysosomal lumen] IDUA Q70* [lysosomal lumen] IDUA W402* [lysosomal lumen] Homo sapiens NCBI Taxonomy 9606 UniProt P35475 GO 0003940 GO molecular function Reactome Database ID Release 78 9631928 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631928 Reactome Database ID Release 78 2206299 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206299 Reactome R-HSA-2206299 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206299.3 1301941 Pubmed 1992 alpha-L-iduronidase mutations (Q70X and P533R) associate with a severe Hurler phenotype Scott, HS Litjens, T Nelson, PV Brooks, DA Hopwood, JJ Morris, CP Hum Mutat 1:333-9 1301196 Pubmed 1992 A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype Scott, HS Litjens, T Hopwood, JJ Morris, CP Hum Mutat 1:103-8 7951228 Pubmed 1994 Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients Bunge, S Kleijer, WJ Steglich, C Beck, M Zuther, C Morris, CP Schwinger, E Hopwood, JJ Scott, HS Gal, A Hum Mol Genet 3:861-6 3.2.1.76 Defective IDUA does not hydrolyse the unsulfated alpha-L-iduronosidic link in DS Defective IDUA does not hydrolyse the unsulfated alpha-L-iduronosidic link in DS Absence of alpha-L-iduronidase (IDUA, MIM:252800), the enzyme responsible for the removal of non-reducing terminal alpha-L-iduronide (Lido) residues during the lysosomal degradation of heparan sulphate (HS) and dermatan sulfate (DS) is the cause of MPS I disorders (MIM:607014). The nonsense mutations, W402X and Q70X and the rarer P553R account for approximately 50% of all MPS I alleles in patients with predominantly European origins (Scott et al. 1992, Bunge et al. 1994, Scott et al. 1992b). There are, however, considerable differences in the frequency of these mutations in patients from Norway and Finland when compared with other Eurpoean countries. In Scandinavia, W402X and Q70X account for 17% and 62% of the MPSI alleles, respectively, while in the other European countries W402X is about 2.5 times more frequent (48%) than Q70X (19%). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-04-26 Reactome DB_ID: 2105025 1 beta-D-IdopA-(1->3)-beta-D-GalpNAc4S-(1->4)-beta-D-GlcpA-(1->3)-beta-D-Galp-(1->3)-beta-D-Galp-(1->4)-beta-D-Xylp [ChEBI:63873] beta-D-IdopA-(1->3)-beta-D-GalpNAc4S-(1->4)-beta-D-GlcpA-(1->3)-beta-D-Galp-(1->3)-beta-D-Galp-(1->4)-beta-D-Xylp ChEBI 63873 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2207701 Reactome Database ID Release 78 9631727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631727 Reactome Database ID Release 78 9036041 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036041 Reactome R-HSA-9036041 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036041.2 3.2.1.76 Defective IDUA does not hydrolyse Heparan sulfate chain(1) Defective IDUA does not hydrolyse Heparan sulfate chain(1) Absence of alpha-L-iduronidase (IDUA, MIM:252800), the enzyme responsible for the removal of non-reducing terminal alpha-L-iduronide (Lido) residues during the lysosomal degradation of heparan sulphate (HS) and dermatan sulfate (DS) is the cause of MPS I disorders (MIM:607014). The nonsense mutations, W402X and Q70X and the rarer P553R account for approximately 50% of all MPS I alleles in patients with predominantly European origins (Scott et al. 1992, Bunge et al. 1994, Scott et al. 1992b). There are, however, considerable differences in the frequency of these mutations in patients from Norway and Finland when compared with other Eurpoean countries. In Scandinavia, W402X and Q70X account for 17% and 62% of the MPSI alleles, respectively, while in the other European countries W402X is about 2.5 times more frequent (48%) than Q70X (19%). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-04-26 Reactome DB_ID: 1605715 1 Reactome DB_ID: 2090033 1 beta-D-IdoA-(1->4)-alpha-D-GlcNS6S-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63666] beta-D-IdoA-(1->4)-alpha-D-GlcNS6S-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63666 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2207701 Reactome Database ID Release 78 9631934 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631934 Reactome Database ID Release 78 9036037 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036037 Reactome R-HSA-9036037 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036037.2 Reactome Database ID Release 78 2206302 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206302 Reactome R-HSA-2206302 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206302.2 13629198 Pubmed 1959 Hereditary disorders of connective tissue McKusick, Victor A Bull N Y Acad Med 35:143-56 1505961 Pubmed 1992 Structure and sequence of the human alpha-L-iduronidase gene Scott, H S Guo, X H Hopwood, J J Morris, C P Genomics 13:1311-3 4112371 Pubmed 1972 Allelism, non-allelism, and genetic compounds among the mucopolysaccharidoses McKusick, Victor A Howell, R R Hussels, I E Neufeld, Elizabeth F Stevenson, R E Lancet 1:993-6 22527994 Pubmed 2012 Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms Campos, Derbis Monaga, Madelyn Metab Brain Dis 27:121-9 MPS II - Hunter syndrome MPS II - Hunter syndrome Mucopolysaccharidosis II (MPS II, Hunter syndrome, MIM:309900) is an X-linked, recessive genetic disorder which therefore primarily affects males. MPS II was first described in 1917, by Major Charles Hunter (Hunter 1917) and is caused by a deficiency (or absence) of iduronate-2-sulfatase (IDS, MIM:300823), which would normally hydrolyse the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin. Without IDS, these GAGs accumulate in the body and are excessively excreted in urine. Although the disease was known since the early 1970s, being the first MPS to be defined clinically in humans, it wasn't until the 1990s that IDS was cloned. It is now known to be localized to Xq28 (Wilson et al. 1991) and contain 9 exons (Flomen et al. 1993) spanning approximately 24 kb (Wilson et al. 1993).<br>Build up can occur in the liver and spleen as well as in the walls and valves of the heart (reduced hepatic and cardiac function, liver/spleen hepatosplenomegaly), airways (leading to obstructive airway disease), all major joints and bones (joint stiffness and skeletal deformities) and in brain (severe mental retardation). The rate of progression and degree of severity of the disorder can be different for each person with MPS II. Severe forms of the disorder can result in death in childhood whereas those with a "milder" form can expect to live to their 20's or 30's. Some patients even survive into their fifth and sixth decades of life (Wraith et al. 2008, Beck 2011). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-04-26 3.1.6.13 Defective IDS does not hydrolyse dermatan sulfate (Chebi:63517 chain) Defective IDS does not hydrolyse dermatan sulfate (Chebi:63517 chain) Mucopolysaccharidosis II (MPS II, Hunter syndrome, MIM:309900) is an X-linked genetic disorder caused by defects in the gene encoding the enzyme iduronate 2-sulfatase (IDS, MIM:300823). This causes an accumulation of the GAGs dermatan sulfate and heparan sulfate and their excessive excretion in urine. MPS II has a broad range of severity with variable mental retardation and life expectancy. This disease has a prevelence of approximately 1 in 170,000 male births (Muenzer et al. 2009). The R468 codon may be a mutational hot-spot, as it has been noted in patients with diverse ethnic origins: R468W (Crotty et al. 1992), R468L and R468Q (Isogai et al. 1998). R443X is also a frequent mutation (Froissart et al. 1998). Authored: Jassal, B, 2012-05-20 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-20 Reactome DB_ID: 2065213 1 beta-D-GalNAc-(1->4)-beta-D-IdoA2S-(1->3)-beta-D-GalNAc4S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63517] beta-D-GalNAc-(1->4)-beta-D-IdoA2S-(1->3)-beta-D-GalNAc4S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63517 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9631735 Ca2+:Ca2+:IDS mutants:IDS mutants [lysosomal lumen] Ca2+:Ca2+:IDS mutants:IDS mutants Reactome DB_ID: 1606834 2 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 Converted from EntitySet in Reactome Reactome DB_ID: 2210362 2 IDS mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity IDS (34-455) R443* [lysosomal lumen] IDS (456-550) R468W [lysosomal lumen] IDS (456-550) R468Q [lysosomal lumen] IDS (456-550) R468L [lysosomal lumen] UniProt P22304 Reactome Database ID Release 78 9631735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631735 Reactome R-HSA-9631735 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631735.1 GO 0004423 GO molecular function Reactome Database ID Release 78 9631895 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631895 Reactome Database ID Release 78 2262743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262743 Reactome R-HSA-2262743 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262743.3 9501270 Pubmed 1998 Mutation analysis in the iduronate-2-sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease) Isogai, K Sukegawa, K Tomatsu, S Fukao, T Song, XQ Yamada, Y Fukuda, Seisuke Orii, T Kondo, N J Inherit Metab Dis 21:60-70 19901005 Pubmed 2009 Multidisciplinary management of Hunter syndrome Muenzer, Joseph Beck, M Eng, C M Escolar, M L Giugliani, R Guffon, N H Harmatz, P Kamin, W Kampmann, C Koseoglu, S T Link, B Martin, R A Molter, D W Muñoz Rojas, M V Ogilvie, J W Parini, R Ramaswami, U Scarpa, M Schwartz, I V Wood, R E Wraith, E Pediatrics 124:e1228-39 9660053 Pubmed 1998 Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients Froissart, R Maire, I Millat, G Cudry, S Birot, AM Bonnet, V Bouton, O Bozon, D Clin Genet 53:362-8 1284597 Pubmed 1992 Mutation R468W of the iduronate-2-sulfatase gene in mild Hunter syndrome (mucopolysaccharidosis type II) confirmed by in vitro mutagenesis and expression Crotty, PL Braun, SE Anderson, RA Whitley, CB Hum Mol Genet 1:755-7 3.1.6.13 Defective IDS does not hydrolyse Heparan sulfate chain(5) Defective IDS does not hydrolyse Heparan sulfate chain(5) Mucopolysaccharidosis II (MPS II, Hunter syndrome, MIM:309900) is an X-linked genetic disorder caused by defects in the gene encoding the enzyme iduronate 2-sulfatase (IDS, MIM:300823). This causes an accumulation of the GAGs dermatan sulfate and heparan sulfate and their excessive excretion in urine. MPS II has a broad range of severity with variable mental retardation and life expectancy. This disease has a prevelence of approximately 1 in 170,000 male births (Muenzer et al. 2009). The R468 codon may be a mutational hot-spot, as it has been noted in patients with diverse ethnic origins: R468W (Crotty et al. 1992), R468L and R468Q (Isogai et al. 1998). R443X is also a frequent mutation (Froissart et al. 1998). Authored: Jassal, B, 2012-05-20 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-20 Reactome DB_ID: 2090080 1 beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63808] beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63808 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9631735 Reactome Database ID Release 78 9631775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631775 Reactome Database ID Release 78 9036046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036046 Reactome R-HSA-9036046 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036046.2 Reactome Database ID Release 78 2206296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206296 Reactome R-HSA-2206296 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206296.2 19979883 Pubmed 1917 A Rare Disease in Two Brothers Hunter, C Proc. R. Soc. Med. 10:104-16 1901826 Pubmed 1991 Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome Wilson, P J Suthers, G K Callen, D F Baker, E Nelson, P V Cooper, A Wraith, J E Sutherland, G R Morris, C P Hopwood, J J Hum. Genet. 86:505-8 18038146 Pubmed 2008 Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy Wraith, JE Scarpa, M Beck, M Bodamer, OA De Meirleir, L Guffon, N Meldgaard Lund, A Malm, G Van der Ploeg, Ans T Zeman, J Eur J Pediatr 167:267-77 21235446 Pubmed 2011 Mucopolysaccharidosis Type II (Hunter Syndrome): clinical picture and treatment Beck, Michael Curr Pharm Biotechnol 12:861-6 8490623 Pubmed 1993 Determination of the organisation of coding sequences within the iduronate sulphate sulphatase (IDS) gene Flomen, R H Green, E P Green, P M Bentley, D R Giannelli, F Hum. Mol. Genet. 2:5-10 8244397 Pubmed 1993 Sequence of the human iduronate 2-sulfatase (IDS) gene Wilson, P J Meaney, C A Hopwood, J J Morris, C P Genomics 17:773-5 MPS IIIA - Sanfilippo syndrome A MPS IIIA - Sanfilippo syndrome A Mucopolysaccharidosis III (MPS III, Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837-838, 1963, no reference). Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome A, MIM:252900) is a rare, autosomal recessive lysosomal storage disease characterised by severe CNS degeneration in early childhood leading to death between 10 and 20 years of age. A deficiency of the enzyme N-sulphoglucosamine sulphohydrolase (SGSH, MIM:605270), which normally hydrolyses the sulfate group from the terminal N-sulphoglucosamine residue of heparan sulfate (HS), leads to the build-up of HS in cells and tissues and its presence in urine (van de Kamp et al. 1981, Yogalingam & Hopwood 2001, de Ruijter et al. 2011). The gene encoding N-sulfoglucosamine sulfohydrolase, SGSH, was cloned in 1995 (Scott et al.1995) and, later, shown to contain 8 exons spanning approximately 11 kb (Karageorgos et al. 1996). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-04-26 3.10.1.1 Defective SGSH does not hydrolyse Heparan sulfate chain(7) Defective SGSH does not hydrolyse Heparan sulfate chain(7) MPS IIIA (Sanfilippo syndrome A, mucopolysaccharidosis IIIA, MIM:252900) is a rare, autosomal recessive lysosomal storage disease. A deficiency of the enzyme N-sulphoglucosamine sulphohydrolase (SGSH, MIM:605270), which normally hydrolyses the sulfate group from the terminal N-sulphoglucosamine residue of heparan sulfate (HS) leads to the build up of HS in cells and tissues, characterised by severe CNS degeneration in early childhood leading to death between 10 and 20 years of age.<br>Four mutations (R74C, R245H, S66W, and 1091delC) are known to be prevalent in Polish (Bunge et al. 1997), Dutch (Weber et al. 1997), Italian (Di Natale et al. 1998), and Spanish (Montfort et al. 1998) populations, respectively. These mutations abolish the activity of SGSH being associated with the classic severe phenotype. Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2090070 1 alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63810] alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63810 Reactome DB_ID: 1605715 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2214337 SGSH mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SGSH S66W [lysosomal lumen] SGSH C1091del [lysosomal lumen] SGSH R245H [lysosomal lumen] SGSH R74C [lysosomal lumen] UniProt P51688 GO 0016250 GO molecular function Reactome Database ID Release 78 9631908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631908 Reactome Database ID Release 78 2263444 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263444 Reactome R-HSA-2263444 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263444.3 9554748 Pubmed 1998 Identification of molecular defects in Italian Sanfilippo A patients including 13 novel mutations Di Natale, P Balzano, N Esposito, S Villani, GR Hum Mutat 11:313-20 9744479 Pubmed 1998 Mutation 1091delC is highly prevalent in Spanish Sanfilippo syndrome type A patients Montfort, M Vilageliu, L Garcia-Giralt, N Guidi, S Coll, MJ Chabás, A Grinberg, D Hum Mutat 12:274-9 9285796 Pubmed 1997 Novel mutations in Sanfilippo A syndrome: implications for enzyme function Weber, B Guo, XH Wraith, JE Cooper, A Kleijer, WJ Bunge, S Hopwood, JJ Hum Mol Genet 6:1573-9 9401012 Pubmed 1997 Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A) Bunge, S Ince, H Steglich, C Kleijer, WJ Beck, M Zaremba, J Van Diggelen, OP Weber, B Hopwood, JJ Gal, A Hum Mutat 10:479-85 3.10.1.1 Defective SGSH does not hydrolyse Heparan sulfate chain(2) Defective SGSH does not hydrolyse Heparan sulfate chain(2) MPS IIIA (Sanfilippo syndrome A, mucopolysaccharidosis IIIA, MIM:252900) is a rare, autosomal recessive lysosomal storage disease. A deficiency of the enzyme N-sulphoglucosamine sulphohydrolase (SGSH, MIM:605270), which normally hydrolyses the sulfate group from the terminal N-sulphoglucosamine residue of heparan sulfate (HS) leads to the build up of HS in cells and tissues, characterised by severe CNS degeneration in early childhood leading to death between 10 and 20 years of age.<br>Four mutations (R74C, R245H, S66W, and 1091delC) are known to be prevalent in Polish (Bunge et al. 1997), Dutch (Weber et al. 1997), Italian (Di Natale et al. 1998), and Spanish (Montfort et al. 1998) populations, respectively. These mutations abolish the activity of SGSH being associated with the classic severe phenotype. Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2090072 1 alpha-D-GlcNS6S-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63805] alpha-D-GlcNS6S-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63805 Reactome DB_ID: 1605715 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2214337 Reactome Database ID Release 78 9631816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631816 Reactome Database ID Release 78 9036050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036050 Reactome R-HSA-9036050 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036050.2 Reactome Database ID Release 78 2206307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206307 Reactome R-HSA-2206307 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206307.2 6796310 Pubmed 1981 Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C) van de Kamp, JJ Niermeijer, MF von Figura, K Giesberts, MA Clin Genet 20:152-60 21235449 Pubmed 2011 Mucopolysaccharidosis type III (Sanfilippo Syndrome): emerging treatment strategies de Ruijter, J Valstar, M J Wijburg, F A Curr Pharm Biotechnol 12:923-30 11668611 Pubmed 2001 Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications Yogalingam, G Hopwood, JJ Hum Mutat 18:264-81 7493035 Pubmed 1995 Cloning of the sulphamidase gene and identification of mutations in Sanfilippo A syndrome Scott, HS Blanch, L Guo, XH Freeman, C Orsborn, A Baker, E Sutherland, GR Morris, CP Hopwood, JJ Nat Genet 11:465-7 8946167 Pubmed 1996 Structure and sequence of the human sulphamidase gene Karageorgos, L E Guo, X H Blanch, L Weber, B Anson, D S Scott, H S Hopwood, J J DNA Res. 3:269-71 MPS IIIB - Sanfilippo syndrome B MPS IIIB - Sanfilippo syndrome B Mucopolysaccharidosis III (Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837838, 1963, no reference). MPS IIIB (Mucopolysaccharidosis type IIIB, MPS IIIB, Sanfilippo syndrome type B; MIM:252920) is an autosomal recessive genetic disorder due to loss of function of alpha-N-acetylglucosaminidase (NAGLU; MIM:609701), involved in the hydrolysis of terminal non-reducing N-acetylglucosamine residues in heparan sulfate (HS) The gene encoding NAGLU was cloned in 1996 by Zhao and colleagues. It contains 6 exons and spans 8.3 kb on chromosome 17q21 (Zhao et al. 1996). MPSIIIB is characterized by severe CNS retardation but only mild somatic disease and death usually occurs in the second or third decade of life (Zhao et al. 1996, Yogalingam & Hopwood 2001, de Ruijter et al. 2011). MPS IIIB shows extensive molecular heterogeneity (Schmidtchen et al. 1998). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-04-26 3.2.1.50 Defective NAGLU does not hydrolyse Heparan sulfate chain(4) Defective NAGLU does not hydrolyse Heparan sulfate chain(4) MPS IIIB (Sanfilippo syndrome B, Mucopolysaccharidosis IIIB, MIM:252920) is an autosomal recessive genetic disorder due to loss of function of alpha-N-acetylglucosaminidase (NAGLU; MIM:609701), normally involved in the hydrolysis of terminal non-reducing N-acetyl-D-glucosamine residues in heparan and heparan sulfate (HS). Mutations that cause severe forms of MPSIIIB are R674C or H (Zhao et al. 1998), R297X (Yogalingam & Hopwood 2001, Zhao et al. 1998) and R626X (Beesley et al 2004). Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2090069 1 alpha-D-GlcNAc-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63807] alpha-D-GlcNAc-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63807 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2219572 NAGLU mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NAGLU R297* [lysosomal lumen] NAGLU R674C [lysosomal lumen] NAGLU R674H [lysosomal lumen] NAGLU R626* [lysosomal lumen] UniProt P54802 GO 0004561 GO molecular function Reactome Database ID Release 78 9631808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631808 Reactome Database ID Release 78 2263496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263496 Reactome R-HSA-2263496 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263496.3 14984474 Pubmed 2004 Sanfilippo B syndrome: molecular defects in Greek patients Beesley, C Moraitou, M Winchester, B Schulpis, K Dimitriou, E Michelakakis, H Clin Genet 65:143-9 9443875 Pubmed 1998 Genotype-phenotype correspondence in Sanfilippo syndrome type B Zhao, HG Aronovich, EL Whitley, CB Am J Hum Genet 62:53-63 3.2.1.50 Defective NAGLU does not hydrolyse heparan chain(2) Defective NAGLU does not hydrolyse heparan chain(2) MPS IIIB (Sanfilippo syndrome B, Mucopolysaccharidosis IIIB, MIM:252920) is an autosomal recessive genetic disorder due to loss of function of alpha-N-acetylglucosaminidase (NAGLU; MIM:609701), normally involved in the hydrolysis of terminal non-reducing N-acetyl-D-glucosamine residues in heparan and heparan sulfate (HS). Mutations that cause severe forms of MPSIIIB are R674C or H (Zhao et al. 1998), R297X (Yogalingam & Hopwood 2001, Zhao et al. 1998) and R626X (Beesley et al 2004). Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 1605715 1 Reactome DB_ID: 2090053 1 alpha-D-GlcNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63645] alpha-D-GlcNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63645 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2219572 Reactome Database ID Release 78 9631896 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631896 Reactome Database ID Release 78 9036052 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036052 Reactome R-HSA-9036052 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036052.2 Reactome Database ID Release 78 2206282 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206282 Reactome R-HSA-2206282 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206282.2 8650226 Pubmed 1996 The molecular basis of Sanfilippo syndrome type B Zhao, HG Li, HH Bach, G Schmidtchen, A Neufeld, Elizabeth F Proc Natl Acad Sci U S A 93:6101-5 9443878 Pubmed 1998 NAGLU mutations underlying Sanfilippo syndrome type B Schmidtchen, A Greenberg, D Zhao, HG Li, HH Huang, Y Tieu, P Zhao, HZ Cheng, S Zhao, Z Whitley, CB Di Natale, P Neufeld, Elizabeth F Am J Hum Genet 62:64-9 MPS IIIC - Sanfilippo syndrome C MPS IIIC - Sanfilippo syndrome C Mucopolysaccharidosis III (Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837838, 1963, no reference). Mucopolysaccharidosis type IIIC (MPS IIIC, Sanfilippo syndrome C; MIM:252930) is an autosomal recessive genetic disorder due to the loss of heparan alpha-glucosaminide N-acetyltransferase (HGSNAT; MIM:610453) that normally acetylates the non-reducing terminal alpha-glucosamine residue of heparan sulfate. The molecular defects underlying MPS IIIC remained unknown for almost three decades due to the low tissue content and instability of HGSNAT. But, during the last decade, the gene was cloned in parallel by two different groups and shown to contain 18 exons and span approximately 62Kb (Fan et al. 2006, Hrebicek et al. 2006). Loss of HGSNAT results in build up of this glycosaminglycan (GAG) in cells and tissues and is characterized by severe central nervous system degeneration but only with mild somatic disease and death occurs typically during the second or third decade of life (Kresse et al. 1978, Klein et al. 1978, Feldhammer et al. 2009, de Ruijter et al. 2011). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-04-26 2.3.1.78 Defective HGSNAT does not acetylate Heparan chain(1) Defective HGSNAT does not acetylate Heparan chain(1) Enzyme misfolding due to missense mutations results in incorrect glycosylation therefore HGSNAT is not targeted to the lysosome and stays in the ER (Feldhammer et al. 2009). This, together with mutations giving rise to nonsense-mediated mRNA decay (Fedele & Hopwood 2010), appear to be the major molecular mechanisms underlying MPSIIIC. More than 50 mutations are known in the HGSNAT gene. Some of them drastically reduce enzyme activity; W403C/A615T double mutant (Fedele & Hopwood 2010), R344C, S518F and R384X (Fedele et al. 2007, Ruijter et al.2008). Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2090045 1 alpha-D-GlcN-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63811] alpha-D-GlcN-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63811 Reactome DB_ID: 76183 1 cytosol GO 0005829 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-CoA acetyl-CoA tetraanion acetyl-coenzyme A(4-) AcCoA(4-) ChEBI 57288 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2245239 lysosomal membrane GO 0005765 HGSNAT mutants [lysosomal membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HGSNAT R384* [lysosomal membrane] W403C/A615T-HGSNAT [lysosomal membrane] HGSNAT R344C [lysosomal membrane] HGSNAT S518F [lysosomal membrane] UniProt Q68CP4 GO 0015019 GO molecular function Reactome Database ID Release 78 9631733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631733 Reactome Database ID Release 78 2263492 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263492 Reactome R-HSA-2263492 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263492.3 18024218 Pubmed 2008 Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands Ruijter, GJ Valstar, MJ van de Kamp, JM van der Helm, RM Durand, S Van Diggelen, OP Wevers, RA Poorthuis, BJ Pshezhetsky, AV Wijburg, FA Mol Genet Metab 93:104-11 17397050 Pubmed 2007 Mutational analysis of the HGSNAT gene in Italian patients with mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Mutation in brief #959. Online Fedele, AO Filocamo, M Di Rocco, M Sersale, G Lübke, T Di Natale, P Cosma, MP Ballabio, A Hum Mutat 28:523 19823584 Pubmed 2009 Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C Feldhammer, M Durand, S Pshezhetsky, AV PLoS One 4:e7434 20583299 Pubmed 2010 Functional analysis of the HGSNAT gene in patients with mucopolysaccharidosis IIIC (Sanfilippo C Syndrome) Fedele, AO Hopwood, JJ Hum Mutat 31:E1574-86 2.3.1.78 Defective HGSNAT does not acetylate Heparan sulfate chain(3) Defective HGSNAT does not acetylate Heparan sulfate chain(3) Enzyme misfolding due to missense mutations results in incorrect glycosylation therefore HGSNAT is not targeted to the lysosome and stays in the ER (Feldhammer et al. 2009). This, together with mutations giving rise to nonsense-mediated mRNA decay (Fedele & Hopwood 2010), appear to be the major molecular mechanisms underlying MPSIIIC. More than 50 mutations are known in the HGSNAT gene. Some of them drastically reduce enzyme activity; W403C/A615T double mutant (Fedele & Hopwood 2010), R344C, S518F and R384X (Fedele et al. 2007, Ruijter et al.2008). Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2090040 1 alpha-D-GlcN-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63806] alpha-D-GlcN-(1->4)-beta-D-IdoA2S-(1->4)-alpha-D-GlcNS3S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63806 Reactome DB_ID: 76183 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2245239 Reactome Database ID Release 78 9631900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631900 Reactome Database ID Release 78 9036056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036056 Reactome R-HSA-9036056 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036056.2 Reactome Database ID Release 78 2206291 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206291 Reactome R-HSA-2206291 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206291.2 33384 Pubmed 1978 Sanfilippo syndrome type C: deficiency of acetyl-CoA:alpha-glucosaminide N-acetyltransferase in skin fibroblasts Klein, U Kresse, H von Figura, K Proc Natl Acad Sci U S A 75:5185-9 16960811 Pubmed 2006 Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C) Fan, X Zhang, H Zhang, S Bagshaw, RD Tropak, MB Callahan, JW Mahuran, DJ Am J Hum Genet 79:738-44 19479962 Pubmed 2009 Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) gene Feldhammer, Matthew Durand, Stéphanie Mrázová, Lenka Boucher, Renée-Myriam Laframboise, Rachel Steinfeld, Robert Wraith, James E Michelakakis, Helen van Diggelen, Otto P Hrebícek, Martin Kmoch, Stanislav Pshezhetsky, Alexey V Hum. Mutat. 30:918-25 17033958 Pubmed 2006 Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome) Hrebícek, M Mrázová, L Seyrantepe, V Durand, S Roslin, NM Nosková, L Hartmannová, H Ivánek, R Cízkova, A Poupetová, H Sikora, J Urinovská, J Stranecký, V Zeman, J Lepage, P Roquis, D Verner, A Ausseil, J Beesley, CE Maire, I Poorthuis, BJ van de Kamp, J van Diggelen, OP Wevers, RA Hudson, TJ Fujiwara, TM Majewski, J Morgan, K Kmoch, S Pshezhetsky, AV Am J Hum Genet 79:807-19 153835 Pubmed 1978 A new biochemical subtype of the Sanfilippo syndrome: characterization of the storage material in cultured fibroblasts of Sanfilippo C patients Kresse, H von Figura, K Klein, U Eur J Biochem 92:333-9 MPS IIID - Sanfilippo syndrome D MPS IIID - Sanfilippo syndrome D Mucopolysaccharidosis III (Sanfilippo syndrome) was described in 1963 by a pediatrician named Sylvester Sanfilippo (J. Pediat. 63: 837-838, 1963, no reference). Mucopolysaccharidosis type IIID (MPS IIID, Sanfilippo syndrome D, MIM:252940) is an autosomal recessive genetic disorder due to the loss of N-acetyl-D-glucosamine 6-sulfatase (GNS; MIM:607664), that hydrolyses the 6-sulfate groups of the N-acetyl-D-glucosamine 6-sulfate units of the glycosaminoglycans (GAGs) heparan sulfate and keratan sulfate. GNS is localized to chromosome 12q14 and has 14 exons spanning 46 kb (Robertson et al. 1988, Mok et al. 2003). Loss of enzyme activity leads to lysosomal accumulation and urinary excretion of heparan sulfate and N-acetylglucosamine 6-sulfate residues (Mok et al. 2003). Keratan sulphate does not accumulate in MPS IIID, as beta-linked N-acetyl-D-glucosamine 6-sulphate can be cleaved by beta-hexosaminidase A (Kresse et al. 1980). This disorder is characterized by progressive mental deterioration but only moderate physical abnormalities and death duing the second or third decade of life, presenting a phenotype similar to MPSIIIA (Jones et al. 1997, de Ruijter et al. 2011). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-04-26 3.1.6.14 Defective GNS does not hydrolyse 6-sulfate from GlcNAc6S Defective GNS does not hydrolyse 6-sulfate from GlcNAc6S Defective GNS does not hydrolyse 6-sulfate from N-acetylglucosamine 6-sulfate of KS Due to the rarity of this disease, only approximately 20 mutations had been described. Recently a study by Valstar et al. revealed 15 of those mutations (Valstar et al. 2010). The group also conducted a literature survey of MPS IIID (MIM:252940). Mutations include R355X (Mok et al. 2003), Q390X (Jansen et al. 2007), Q272X (Beesley et al. 2007) and S94I (Valstar et al. 2010). Other mutations are not detailed here but can be referenced in the Valstar et al. review (Valstar et al. 2010). Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Matos, Liliana, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2104995 1 beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp [ChEBI:63851] beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp ChEBI 63851 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2245240 GNS mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GNS Q390* [lysosomal lumen] GNS R355* [lysosomal lumen] GNS S94I [lysosomal lumen] GNS Q272* [lysosomal lumen] UniProt P15586 GO 0008449 GO molecular function Reactome Database ID Release 78 9631792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631792 Reactome Database ID Release 78 2263495 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263495 Reactome R-HSA-2263495 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263495.3 12573255 Pubmed 2003 Genomic basis of mucopolysaccharidosis type IIID (MIM 252940) revealed by sequencing of GNS encoding N-acetylglucosamine-6-sulfatase Mok, A Cao, H Hegele, RA Genomics 81:1-5 20232353 Pubmed 2010 Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations Valstar, MJ Bertoli-Avella, AM Wessels, MW Ruijter, GJ de Graaf, B Olmer, R Elfferich, P Neijs, S Kariminejad, R Suheyl Ezgü, F Tokatli, A Czartoryska, B Bosschaart, AN van den Bos-Terpstra, F Puissant, H Bürger, F Omran, H Eckert, D Filocamo, M Simeonov, E Willems, PJ Wevers, RA Niermeijer, MF Halley, DJ Poorthuis, BJ van Diggelen, OP Hum Mutat 31:E1348-60 16990043 Pubmed 2007 Identification and characterisation of an 8.7 kb deletion and a novel nonsense mutation in two Italian families with Sanfilippo syndrome type D (mucopolysaccharidosis IIID) Beesley, CE Concolino, D Filocamo, M Winchester, BG Strisciuglio, P Mol Genet Metab 90:77-80 17998446 Pubmed 2007 Sanfilippo syndrome type D: natural history and identification of 3 novel mutations in the GNS Gene Jansen, AC Cao, H Kaplan, P Silver, K Leonard, G De Meirleir, L Lissens, W Liebaers, I Veilleux, M Andermann, F Hegele, RA Andermann, E Arch Neurol 64:1629-34 Reactome Database ID Release 78 2206305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206305 Reactome R-HSA-2206305 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206305.2 6450420 Pubmed 1980 Sanfilippo disease type D: deficiency of N-acetylglucosamine-6-sulfate sulfatase required for heparan sulfate degradation Kresse, H Paschke, E von Figura, K Gilberg, W Fuchs, W Proc Natl Acad Sci U S A 77:6822-6 3391615 Pubmed 1988 Chromosomal localization of the gene for human glucosamine-6-sulphatase to 12q14 Robertson, D A Callen, D F Baker, E G Morris, C P Hopwood, J J Hum. Genet. 79:175-8 9329460 Pubmed 1997 Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics Jones, M Z Alroy, J Rutledge, J C Taylor, J W Alvord, E C Toone, J Applegarth, D Hopwood, J J Skutelsky, E Ianelli, C Thorley-Lawson, D Mitchell-Herpolsheimer, C Arias, A Sharp, P Evans, W Sillence, D Cavanagh, K T J. Neuropathol. Exp. Neurol. 56:1158-67 MPS IV - Morquio syndrome A MPS IV - Morquio syndrome A Mucopolysaccharidosis IV A (MPS IVA, MPS4A, Morquio's syndrome, Morquio's; MIM:253000) is a rare, autosomal recessive mucopolysaccharide storage disease, first described simultaneously in 1929 by L Morquio (Morquio L, Sur une forme de distrophie familiale, Bull Soc Pediat, Paris, 27, 1929, 145-152) and JF Brailsford (Brailsford, JF, Chondro-osteo-dystrophy: roentgenographic and clinical features of child with dislocation of vertebrae, Am j Surg, 7, 1929, 404-410). MPSIVA is caused by a deficiency in N-acetylgalactosamine 6-sulfatase (GALNS; MIM:612222) which normally hydrolyses 6-sulfate groups of N-acetylgalactosamine 6-sulfate units of chondroitin sulfate (CS) and of galactose 6-sulfate units of keratan sulfate (KS) (Matalon et al. 1974). The result is accumulation of KS/DS in cells and overexcretion in urine. Severe osteochondrodysplasia is a commonly seen phenotype for this disease. The severity of the disease is variable but severe cases limits lifespan to their 20's or 30's (Prat et al. 2008, Tomatsu et al. 2011). The gene coding for human GALNS was mapped to chromosome 16q24.3 (Masuno et al. 1993) and its structure described at the same time by two independent groups as comprising 14 exons and spanning approximately 40-50 kb (Nakashima et al.1994, Morris et al.1994). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-04-26 3.1.6.4 Defective GALNS does not hydrolyse sulfate from Gal6S in keratan sulfate Defective GALNS does not hydrolyse sulfate from Gal6S in keratan sulfate From a recent review of mutations for MPSIVA (MIM:253000) (Tomatsu et al. 2005), almost 80% of mutations in N-acetylgalactosamine 6-sulfatase (GALNS; MIM:612222) were missense mutations and of these, the most common ones are R386C, G301C and I113F. Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2105007 1 beta-D-Galp6S-(1->4)-beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp [ChEBI:63846] beta-D-Galp6S-(1->4)-beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp ChEBI 63846 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2245328 GALNS mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GALNS R386C [lysosomal lumen] GALNS I113F [lysosomal lumen] GALNS G301C [lysosomal lumen] UniProt P34059 GO 0043890 GO molecular function Reactome Database ID Release 78 9631848 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631848 Reactome Database ID Release 78 2263490 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2263490 Reactome R-HSA-2263490 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2263490.3 16287098 Pubmed 2005 Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A) Tomatsu, S Montaño, AM Nishioka, T Gutierrez, MA Peña, OM Tranda Firescu, GG Lopez, P Yamaguchi, S Noguchi, A Orii, T Hum Mutat 26:500-12 Reactome Database ID Release 78 2206290 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206290 Reactome R-HSA-2206290 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206290.1 4218100 Pubmed 1974 Morquio's syndrome: deficiency of a chondroitin sulfate N-acetylhexosamine sulfate sulfatase Matalon, R Arbogast, B Justice, P Brandt, IK Dorfman, A Biochem Biophys Res Commun 61:759-65 21506915 Pubmed 2011 Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment Tomatsu, S Montaño, A M Oikawa, H Smith, M Barrera, L Chinen, Y Thacker, M M Mackenzie, W G Suzuki, Y Orii, T Curr Pharm Biotechnol 12:931-45 8001980 Pubmed 1994 Morquio A syndrome: cloning, sequence, and structure of the human N-acetylgalactosamine 6-sulfatase (GALNS) gene Morris, C P Guo, X H Apostolou, S Hopwood, J J Scott, H S Genomics 22:652-4 8020961 Pubmed 1994 Mucopolysaccharidosis IV A: molecular cloning of the human N-acetylgalactosamine-6-sulfatase gene (GALNS) and analysis of the 5'-flanking region Nakashima, Y Tomatsu, S Hori, T Fukuda, S Sukegawa, K Kondo, N Suzuki, Y Shimozawa, N Orii, T Genomics 20:99-104 18456538 Pubmed 2008 Morquio syndrome: diagnosis in an adult Prat, C Lemaire, O Bret, J Zabraniecki, L Fournié, B Joint Bone Spine 75:495-8 8325655 Pubmed 1993 Mucopolysaccharidosis IV A: assignment of the human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene to chromosome 16q24 Masuno, M Tomatsu, S Nakashima, Y Hori, T Fukuda, S Masue, M Sukegawa, K Orii, T Genomics 16:777-8 MPS IV - Morquio syndrome B MPS IV - Morquio syndrome B Defects in beta-galactosidase (GLB1; MIM:611458) can result in GM1 gangliosidosis (GM1; MIM:230500) (Nishimoto et al. 1991) (not described here), with several phenotypes indicating mental deterioration, as well as in mucopolysaccharidosis IVB, a characteristic mucopolysaccharidosis with no neurological symptoms (Callahan 1999).<br><br>Mucopolysaccharidosis IVB (MPS IVB, Morquio's syndrome B; MIM:253010) is a rare, autosomal recessive mucopolysaccharide storage disease characterized by intracellular accumulation of keratan sulfate (KS), skeletal dysplasia and corneal clouding. There is no central nervous system involvement, intelligence is normal and there is increased KS excretion in urine (Suzuki et al. "Beta-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease", p3775-3809 in Stryer et al. 2001). MPSIVB is caused by a defect in betagalactosidase (GLB1), which normally cleaves terminal galactosyl residues from glycosaminoglycans, gangliosides and glycoproteins. The GLB1 gene spans 62.5 kb and contains 16 exons (Oshima et al.1988, Santamaria et al. 2007) and maps to chromosome 3p21.33 (Takano & Yamanouchi 1993).<br> Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-04-26 3.2.1.23 Defective GLB1 does not hydrolyse a glycosaminoglycan Defective GLB1 does not hydrolyse a glycosaminoglycan Defects in beta-galactosidase (GLB1, MIM:611458) result in galactose moieties not being hydrolysed from keratan sulfate (KS) or the GAG linker chain, a tetrasccharide sequence required for some GAG biosyntheses to take place. Mucopolysaccharidosis IV B (MPSIVB, Morquio's syndrome B; MIM:253010) is the result of GLB1 deficiency.<br>GLB1 mutations causing severe phenotypes are R482C (Ishii et al. 1995), W509C (Oshima et al. 1991), Y83C (Santamaria et al. 2006) and W273L Paschke et al. 2001. Mild phenotypes where a partial loss of enzyme activity occurs can involve the mutants G438E, N484K, T500A (Bagshaw et al. 2002) and Y83H (Ishii et al. 1995). These mild phenotype mutants are not detailed here. Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 1605715 1 Reactome DB_ID: 2104997 1 beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp [ChEBI:63850] beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp ChEBI 63850 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2262737 GLB1 mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GLB1 W273L [lysosomal lumen] GLB1 Y83C [lysosomal lumen] GLB1 W509C [lysosomal lumen] GLB1 R482C [lysosomal lumen] UniProt P16278 GO 0004565 GO molecular function Reactome Database ID Release 78 9631738 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631738 Reactome Database ID Release 78 2265534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2265534 Reactome R-HSA-2265534 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2265534.3 1928092 Pubmed 1991 Human beta-galactosidase gene mutations in morquio B disease Oshima, A Yoshida, K Shimmoto, M Fukuhara, Y Sakuraba, H Suzuki, Y Am J Hum Genet 49:1091-3 12393180 Pubmed 2002 Novel mutations (Asn 484 Lys, Thr 500 Ala, Gly 438 Glu) in Morquio B disease Bagshaw, Richard D Zhang, Sunqu Hinek, Alina Skomorowski, Marie Anne Whelan, Donald Clarke, Joe T R Callahan, John W Biochim. Biophys. Acta 1588:247-53 7586649 Pubmed 1995 Clinical and molecular analysis of a Japanese boy with Morquio B disease Ishii, N Oohira, T Oshima, A Sakuraba, H Endo, F Matsuda, I Sukegawa, K Orii, T Suzuki, Y Clin. Genet. 48:103-8 11511921 Pubmed 2001 Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B Paschke, E Milos, I Kreimer-Erlacher, H Hoefler, G Beck, M Hoeltzenbein, M Kleijer, W Levade, T Michelakakis, H Radeva, B Hum. Genet. 109:159-66 16941474 Pubmed 2006 Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies Santamaria, Raül Chabás, Amparo Coll, Maria Josep Miranda, Clara Sa Vilageliu, Lluïsa Grinberg, Daniel Hum. Mutat. 27:1060 3.2.1.23 Defective GLB1 does not hydrolyse linker chain(2) Defective GLB1 does not hydrolyse linker chain(2) Defects in beta-galactosidase (GLB1, MIM:611458) result in galactose moieties not being hydrolysed from keratan sulfate (KS) or the GAG linker chain, a tetrasccharide sequence required for some GAG biosyntheses to take place. Mucopolysaccharidosis IV B (MPSIVB, Morquio's syndrome B; MIM:253010) is the result of GLB1 deficiency.<br>GLB1 mutations causing severe phenotypes are R482C (Ishii et al. 1995), W509C (Oshima et al. 1991), Y83C (Santamaria et al. 2006) and W273L Paschke et al. 2001. Mild phenotypes where a partial loss of enzyme activity occurs can involve the mutants G438E, N484K, T500A (Bagshaw et al. 2002) and Y83H (Ishii et al. 1995). These mild phenotype mutants are not detailed here. Authored: Jassal, B, 2012-05-21 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-05-21 Reactome DB_ID: 2090075 1 beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63503] beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63503 Reactome DB_ID: 1605715 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2262737 Reactome Database ID Release 78 9631857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631857 Reactome Database ID Release 78 9036061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036061 Reactome R-HSA-9036061 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036061.3 Reactome Database ID Release 78 2206308 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206308 Reactome R-HSA-2206308 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206308.2 0079130356 ISBN 2001 Beta-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease Suzuki, Y Oshima, A Nanba, E The Metabolic and Molecular Bases of Inherited Disease, 8th ed (Book): 3775-3809 10571006 Pubmed 1999 Molecular basis of GM1 gangliosidosis and Morquio disease, type B. Structure-function studies of lysosomal beta-galactosidase and the non-lysosomal beta-galactosidase-like protein Callahan, J W Biochim. Biophys. Acta 1455:85-103 7693577 Pubmed 1993 Assignment of human beta-galactosidase-A gene to 3p21.33 by fluorescence in situ hybridization Takano, T Yamanouchi, Y Hum. Genet. 92:403-4 3143362 Pubmed 1988 Cloning, sequencing, and expression of cDNA for human beta-galactosidase Oshima, A Tsuji, A Nagao, Y Sakuraba, H Suzuki, Y Biochem. Biophys. Res. Commun. 157:238-44 1909089 Pubmed 1991 GM1-gangliosidosis (genetic beta-galactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients Nishimoto, J Nanba, E Inui, K Okada, S Suzuki, K Am. J. Hum. Genet. 49:566-74 17309651 Pubmed 2007 Identification of 14 novel GLB1 mutations, including five deletions, in 19 patients with GM1 gangliosidosis from South America Santamaria, R Blanco, M Chabas, A Grinberg, D Vilageliu, L Clin. Genet. 71:273-9 MPS VI - Maroteaux-Lamy syndrome MPS VI - Maroteaux-Lamy syndrome Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, polydystrophic dwarfism; MIM:253200) is an autosomal recessive lysosomal storage disorder caused by a deficiency in arylsulfatase B (ARSB, N-acetyl-galactosamine 4-sulfatase; MIM:611542). It is named after two French physicians, Pierre Maroteaux and Maurice Emil Joseph Lamy. Maroteaux first described this disorder as a novel dysostosis associated with increased urinary excretion of chondroitin sulfate (CS; Maroteaux et al. 1963). The gene encoding ARSB is mapped to chromosome 5q11-q13 (Fidzianska et al. 1984) and contains 8 exons spanning about 206 kb (Karangeorgos et al. 2007). Defective ARSB results in build up of dermatan sulfate (DS) and chondroitin sulfate (CS) in soft tissues causing compression and blockages in blood vessels, nerves, trachea, corneal clouding and disrupting normal bone development. Symptoms are similar to MPS I but with normal intelligence generally (Rapini et al. 2007, Valayannopoulos et al. 2010). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Edited: Jassal, B, 2012-04-26 3.1.6.12 Defective ARSB does not hydrolyse C4S/C6S chains Defective ARSB does not hydrolyse C4S/C6S chains Arylsulfatase B using calcium cofactor (ARSB:Ca2+) hydrolyses sulfate from N-acetylgalactosamine 4-sulfate (or 6-sulfate) units (GalNAc 4-sulfate or GalNAc 6-sulfate) within chondroitin sulfate. Defects in ARSB cause mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, polydystrophic dwarfism; MIM:253200), an autosomal recessive lysosomal storage disorder. Severe forms of the disease are caused by the ARSB mutations Y86del (Karageorgos et al. 2004), P116H (Villani et al. 1999), C117R (Jin et al. 1992), G144R (Isbrandt et al. 1994) and R95Q/H393P (Litjens et al. 1996). Authored: Jassal, B, 2012-05-28 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-05-28 Reactome DB_ID: 1605715 1 Converted from EntitySet in Reactome Reactome DB_ID: 2065251 1 C4S/C6S chains [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity C4S chain [lysosomal lumen] C6S chain [lysosomal lumen] ChEBI 63513 ChEBI 63512 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9631731 ARSB mutants:Ca2+ [lysosomal lumen] ARSB mutants:Ca2+ Converted from EntitySet in Reactome Reactome DB_ID: 2314611 1 ARSB mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ARSB P116H [lysosomal lumen] ARSB Y86del [lysosomal lumen] ARSB C117R [lysosomal lumen] ARSB G144R [lysosomal lumen] ARSB H393P [lysosomal lumen] ARSB R95Q [lysosomal lumen] UniProt P15848 Reactome DB_ID: 1606834 1 Reactome Database ID Release 78 9631731 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631731 Reactome R-HSA-9631731 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631731.1 GO 0003943 GO molecular function Reactome Database ID Release 78 9631784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631784 Reactome Database ID Release 78 2282889 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2282889 Reactome R-HSA-2282889 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2282889.3 1550123 Pubmed 1992 Mucopolysaccharidosis type VI: identification of three mutations in the arylsulfatase B gene of patients with the severe and mild phenotypes provides molecular evidence for genetic heterogeneity Jin, W D Jackson, C E Desnick, R J Schuchman, E H Am. J. Hum. Genet. 50:795-800 8116615 Pubmed 1994 Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): six unique arylsulfatase B gene alleles causing variable disease phenotypes Isbrandt, D Arlt, G Brooks, D A Hopwood, J J von Figura, K Peters, C Am. J. Hum. Genet. 54:454-63 14974081 Pubmed 2004 Mutational analysis of mucopolysaccharidosis type VI patients undergoing a trial of enzyme replacement therapy Karageorgos, L Harmatz, P Simon, J Pollard, A Clements, P R Brooks, D A Hopwood, John J Hum. Mutat. 23:229-33 10036316 Pubmed 1999 Maroteaux-lamy syndrome: five novel mutations and their structural localization Villani, G R Balzano, N Vitale, D Saviano, M Pavone, V Di Natale, P Biochim. Biophys. Acta 1453:185-92 8651289 Pubmed 1996 Identification, expression, and biochemical characterization of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients Litjens, T Brooks, D A Peters, C Gibson, G J Hopwood, J J Am. J. Hum. Genet. 58:1127-34 3.1.6.12 Defective ARSB does not hydrolyse DS Defective ARSB does not hydrolyse DS Arylsulfatase B using calcium cofactor (ARSB:Ca2+) hydrolyses sulfate from N-acetylgalactosamine 4-sulfate (or 6-sulfate) units (GalNAc 4-sulfate or GalNAc 6-sulfate) within chondroitin sulfate (represented here by Chebi:63519 chain). Defects in ARSB cause mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, polydystrophic dwarfism; MIM:253200), an autosomal recessive lysosomal storage disorder. Severe forms of the disease are caused by the ARSB mutations Y86del (Karageorgos et al. 2004), P116H (Villani et al. 1999), C117R (Jin et al. 1992), G144R (Isbrandt et al. 1994) and R95Q/H393P (Litjens et al. 1996). Authored: Jassal, B, 2012-05-28 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-05-28 Reactome DB_ID: 2065231 1 beta-D-GalNAc4S-(1->4)-beta-D-IdoA2S-(1->3)-beta-D-GalNAc4S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63519] beta-D-GalNAc4S-(1->4)-beta-D-IdoA2S-(1->3)-beta-D-GalNAc4S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63519 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9631731 Reactome Database ID Release 78 9631730 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631730 Reactome Database ID Release 78 9036065 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036065 Reactome R-HSA-9036065 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036065.2 Reactome Database ID Release 78 2206285 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206285 Reactome R-HSA-2206285 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206285.2 6467990 Pubmed 1984 Assignment of the gene for human arylsulfatase B, ARSB, to chromosome region 5p11----5qter Fidzianska, E Abramowicz, T Czartoryska, B Glogowska, I Gorska, D Rodo, M Cytogenet. Cell Genet. 38:150-1 14091597 Pubmed 1963 [A NEW DYSOSTOSIS WITH URINARY ELIMINATION OF CHONDROITIN SULFATE B] MAROTEAUX, P Leveque, B MARIE, J Lamy, M Presse Med 71:1849-52 1416029990 ISBN 2007 Dermatology: 2-Volume Set Rapini, RP Bolognia, JL Jorizzo, JL Dermatology: 2-Volume Set (Book) 20385007 Pubmed 2010 Mucopolysaccharidosis VI Valayannopoulos, Vassili Nicely, Helen Harmatz, Paul Turbeville, Sean Orphanet J Rare Dis 5:5 17458871 Pubmed 2007 Mutational analysis of 105 mucopolysaccharidosis type VI patients Karageorgos, Litsa Brooks, Doug A Pollard, Anthony Melville, Elizabeth L Hein, Leanne K Clements, Peter R Ketteridge, David Swiedler, Stuart J Beck, Michael Giugliani, Roberto Harmatz, Paul Wraith, James E Guffon, Nathalie Leão Teles, Elisa Sá Miranda, M Clara Hopwood, John J Hum. Mutat. 28:897-903 MPS VII - Sly syndrome MPS VII - Sly syndrome Mucopolysaccharidosis type VII (MPS VII, Sly syndrome, beta-glucuronidase deficiency; MIM:253220) is an autosomal recessive lysosomal storage disease characterized by a deficiency of the enzyme beta-glucuronidase (GUSB; MIM:611499) which would normally cleave glucuronide residues from dematan sulphate, keratan sulphate and chondroitin sulphate, resulting in build up of these GAGs in cells and tissues (Sly et al. 1973). The gene encoding GUSB is 21 kb long, contains 12 exons and gives rise to two different types of cDNAs, through an alternate splicing mechanism (Miller et al. 1990). It maps to 7q11.21-q11.22 (Speleman et al. 1996). The phenotype is highly variable, ranging from severe causing death, non-immune hydrops fetalis (Vervoort et al. 1996) to mild forms with survival into adulthood (Storch et al. 2003). Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al. 1993, Tomatsu et al. 2009). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Reviewed: Ashworth, Jane, 2012-08-28 Edited: Jassal, B, 2012-04-26 3.2.1.31 Defective GUSB does not hydrolyse (HA)2 Defective GUSB does not hydrolyse (HA)2 Tetrameric lysosomal enzyme beta-glucuronidase (GUSB tetramer) hydrolyses glucuronate from the HA tetrasaccharide (HA(2)) resulting in the single sugars glucuronic acid and N-acetylglucosamine. Defects in beta-glucuronidase (GUSB; MIM:611499) cause mucopolysaccharidosis type VII (MPS VII, Sly syndrome, beta-glucuronidase deficiency; MIM:253220), an autosomal recessive lysosomal storage disease. Mutations causing severe forms of the disease are R356* (Shipley et al. 1993), A354V and R611W (Wu & Sly 1993), S52F (Vervoot et al. 1997) and R216W (Vervoort et al. 1996). Authored: Jassal, B, 2012-06-13 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-06-13 Reactome DB_ID: 2160866 1 (HA)2 [lysosomal lumen] (HA)2 Hyaluronan Hyaluronic acid Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2318394 GUSB mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GUSB R611W [lysosomal lumen] GUSB R216W [lysosomal lumen] GUSB R356* [lysosomal lumen] GUSB A354V [lysosomal lumen] GUSB S52F [lysosomal lumen] UniProt P08236 GO 0004566 GO molecular function Reactome Database ID Release 78 9631796 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631796 Reactome Database ID Release 78 2318373 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318373 Reactome R-HSA-2318373 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318373.3 8111413 Pubmed 1993 Mutational studies in a patient with the hydrops fetalis form of mucopolysaccharidosis type VII Wu, B M Sly, W S Hum. Mutat. 2:446-57 7680524 Pubmed 1993 Mutational analysis of a patient with mucopolysaccharidosis type VII, and identification of pseudogenes Shipley, J M Klinkenberg, M Wu, B M Bachinsky, D R Grubb, J H Sly, W S Am. J. Hum. Genet. 52:517-26 9099834 Pubmed 1997 Molecular analysis of the beta-glucuronidase gene: novel mutations in mucopolysaccharidosis type VII and heterogeneity of the polyadenylation region Vervoort, R Buist, N R Kleijer, W J Wevers, R Fryns, J P Liebaers, I Lissens, W Hum. Genet. 99:462-8 8644704 Pubmed 1996 Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII Vervoort, R Islam, M R Sly, W S Zabot, M T Kleijer, W J Chabas, A Fensom, A Young, E P Liebaers, I Lissens, W Am. J. Hum. Genet. 58:457-71 3.2.1.31 Defective GUSB does not hydrolyse GlcA-β1,3-GlcNAc Defective GUSB does not hydrolyse GlcA-β1,3-GlcNAc Tetrameric lysosomal enzyme beta-glucuronidase (GUSB tetramer) hydrolyses glucuronate from the HA disaccharide GlcA-β1,3-GlcNAc resulting in the single sugars glucuronic acid and N-acetylglucosamine. Defects in beta-glucuronidase (GUSB; MIM:611499) cause mucopolysaccharidosis type VII (MPS VII, Sly syndrome, beta-glucuronidase deficiency; MIM:253220), an autosomal recessive lysosomal storage disease. Mutations causing severe forms of the disease are R356* (Shipley et al. 1993), A354V and R611W (Wu & Sly 1993), S52F (Vervoot et al. 1997) and R216W (Vervoort et al. 1996). Authored: Jassal, B, 2012-06-13 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-06-13 Reactome DB_ID: 1605715 1 Reactome DB_ID: 2162224 1 beta-D-GlcpA-(1->3)-D-GlcpNAc [ChEBI:64024] beta-D-GlcpA-(1->3)-D-GlcpNAc ChEBI 64024 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2318394 Reactome Database ID Release 78 9631734 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631734 Reactome Database ID Release 78 9036068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036068 Reactome R-HSA-9036068 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036068.2 3.2.1.31 Defective GUSB does not hydrolyse CS/HS precursor Defective GUSB does not hydrolyse CS/HS precursor Tetrameric lysosomal enzyme beta-glucuronidase (GUSB tetramer) hydrolyses glucuronate from heparan or the linker chain. Defects in beta-glucuronidase (GUSB; MIM:611499) cause mucopolysaccharidosis type VII (MPS VII, Sly syndrome, beta-glucuronidase deficiency; MIM:253220), an autosomal recessive lysosomal storage disease. Mutations causing severe forms of the disease are R356* (Shipley et al. 1993), A354V and R611W (Wu & Sly 1993), S52F (Vervoot et al. 1997) and R216W (Vervoort et al. 1996). Authored: Jassal, B, 2012-06-13 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-06-13 Reactome DB_ID: 2065212 1 beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63505] beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI 63505 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2318394 Reactome Database ID Release 78 9631951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631951 Reactome Database ID Release 78 9036070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036070 Reactome R-HSA-9036070 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036070.2 Reactome Database ID Release 78 2206292 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206292 Reactome R-HSA-2206292 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206292.3 19224584 Pubmed 2009 Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome) Tomatsu, S Montaño, AM Dung, VC Grubb, JH Sly, William S Hum Mutat 30:511-9 4265197 Pubmed 1973 Beta glucuronidase deficiency: report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis Sly, W S Quinton, B A McAlister, W H Rimoin, David L J. Pediatr. 82:249-57 2347593 Pubmed 1990 Cloning and characterization of the human beta-glucuronidase gene Miller, R D Hoffmann, J W Powell, P P Kyle, J W Shipley, J M Bachinsky, D R Sly, W S Genomics 7:280-3 8565635 Pubmed 1996 Localization by fluorescence in situ hybridization of the human functional beta-glucuronidase gene (GUSB) to 7q11.21 --> q11.22 and two pseudogenes to 5p13 and 5q13 Speleman, F Vervoort, R van Roy, N Liebaers, I Sly, W S Lissens, W Cytogenet. Cell Genet. 72:53-5 12522561 Pubmed 2003 Mutational analysis in longest known survivor of mucopolysaccharidosis type VII Storch, Stephan Wittenstein, Birgit Islam, Rafiqul Ullrich, K Sly, William S Braulke, T Hum. Genet. 112:190-4 MPS IX - Natowicz syndrome MPS IX - Natowicz syndrome Mucopolysaccharidosis type IX (MPS IX, Natowicz syndrome, Hyaluronidase deficiency, MIM:601492) is a rare lysosomal storage disease characterized by high hyaluronan (HA) concentration in the serum resulting from deficiency in hyaluronidase 1 (HYAL1, MIM:607071) which normally hydrolyses 1-4 linkages between N-acetylglucosamine (GlcNAc) and D-glucuronate (GlcA) residues. Symptoms of MPS IX are periodically painful soft tissue masses around the joints, acquired short stature and erosion of the hip joint, although joint movement and intelligence are normal (Natowicz et al. 1996, Triggs-Raine et al. 1999). Authored: Jassal, B, 2012-04-26 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-04-26 3.2.1.35 Defective HYAL1 does not hydrolyse Chondroitin chains Defective HYAL1 does not hydrolyse Chondroitin chains Hyaluronidase 1 (HYAL1) hydrolyses 1-4 linkages between GalNAc and D-glucuronate residues in chondroitin (or dermatan). It also hydrolyses this linkage in hyaluronate, another glycosaminoglycan (GAG) composed of repeating disaccharide units but the only one which is non-sulfated. Defects in HYAL1 (MIM:607071) cause mucopolysaccharidosis type IX (MPS IX, Natowicz syndrome, Hyaluronidase deficiency, MIM:601492), a rare lysosomal storage disease. Triggs-Raine et al. identified a patient with two mutations in HYAL1 alleles, a nonconservative amino acid substitution (Glu268Lys) and a complex intragenic rearrangement (1361del37ins14) that results in a premature termination codon (Triggs-Raine et al. 1999). Authored: Jassal, B, 2012-06-14 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-06-14 Converted from EntitySet in Reactome Reactome DB_ID: 2065257 1 Chondroitin chains [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ChEBI:63515 chain [lysosomal lumen] Chondroitin chain [lysosomal lumen] C4S chain [lysosomal lumen] C6S chain [lysosomal lumen] ChEBI 63515 ChEBI 63511 Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318714 UniProt:Q12794 HYAL1 HYAL1 HYAL1 LUCA1 FUNCTION May have a role in promoting tumor progression. May block the TGFB1-enhanced cell growth.TISSUE SPECIFICITY Highly expressed in the liver, kidney and heart. Weakly expressed in lung, placenta and skeletal muscle. No expression detected in adult brain. Isoform 1 is expressed only in bladder and prostate cancer cells, G2/G3 bladder tumor tissues and lymph node specimens showing tumor invasive tumors cells. Isoform 3, isoform 4, isoform 5 and isoform 6 are expressed in normal bladder and bladder tumor tissues.SIMILARITY Belongs to the glycosyl hydrolase 56 family. UniProt Q12794 Deletion of residues 251 to 262 Insertion of residues 270 to 273 at 251 from UniProt:Q12794 HYAL1 251 EQUAL L-glutamine 263 replaced with L-arginine 263 EQUAL L-glutamine removal [MOD:01637] L-histidine 264 replaced with L-isoleucine 264 EQUAL L-histidine removal [MOD:01639] L-arginine 265 replaced with L-proline 265 EQUAL L-arginine removal [MOD:01632] L-valine 266 replaced with L-cysteine 266 EQUAL L-valine removal [MOD:01650] L-alanine 267 replaced with glycine 267 EQUAL L-alanine removal [MOD:01631] L-glutamic acid 268 replaced with L-lysine 268 EQUAL L-glutamic acid removal [MOD:01636] L-alanine 269 replaced with glycine 269 EQUAL L-phenylalanine 270 replaced with L-isoleucine 270 EQUAL L-phenylalanine removal [MOD:01644] L-arginine 271 replaced with L-proline 271 EQUAL L-valine 272 replaced with L-cysteine 272 EQUAL L-alanine 273 replaced with glycine 273 EQUAL L-valine 274 replaced with L-cysteine 274 EQUAL L-alanine 275 replaced with glycine 275 EQUAL L-alanine 276 replaced with L-cysteine 276 EQUAL glycine 277 replaced with L-tryptophan 277 EQUAL glycine removal [MOD:01638] Chain Coordinates 22 EQUAL 277 EQUAL GO 0004415 GO molecular function Reactome Database ID Release 78 9631747 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631747 Reactome Database ID Release 78 2318585 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318585 Reactome R-HSA-2318585 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318585.3 10339581 Pubmed 1999 Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX Triggs-Raine, B Salo, T J Zhang, H Wicklow, B A Natowicz, M R Proc. Natl. Acad. Sci. U.S.A. 96:6296-300 3.2.1.35 Defective HYAL1 does not hydrolyse (HA)50 Defective HYAL1 does not hydrolyse (HA)50 In the acidic environment of the lysosome, hyaluronidase 1 (HYAL1) is able to hydrolyse large 20kDa HA fragments (approximately 50 disaccharide units) to 800 Da fragments (2 disaccharide units). Defects in HYAL1 (MIM:607071) cause mucopolysaccharidosis type IX (MPS IX, Natowicz syndrome, Hyaluronidase deficiency, MIM:601492), a rare lysosomal storage disease. Triggs-Raine et al. identified a patient with two mutations in HYAL1 alleles, a nonconservative amino acid substitution (Glu268Lys) and a complex intragenic rearrangement (1361del37ins14) that results in a premature termination codon (Triggs-Raine et al. 1999). Authored: Jassal, B, 2012-06-14 Reviewed: Coutinho, Maria, 2012-08-27 Reviewed: Alves, Sandra, 2012-08-27 Edited: Jassal, B, 2012-06-14 Reactome DB_ID: 2160864 1 (HA)50 [lysosomal lumen] (HA)50 Hyaluronan Hyaluronic acid Reactome DB_ID: 1605715 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318714 Deletion of residues 251 to 262 Insertion of residues 270 to 273 at 251 from UniProt:Q12794 HYAL1 251 EQUAL L-glutamine 263 replaced with L-arginine 263 EQUAL L-histidine 264 replaced with L-isoleucine 264 EQUAL L-arginine 265 replaced with L-proline 265 EQUAL L-valine 266 replaced with L-cysteine 266 EQUAL L-alanine 267 replaced with glycine 267 EQUAL L-glutamic acid 268 replaced with L-lysine 268 EQUAL L-alanine 269 replaced with glycine 269 EQUAL L-phenylalanine 270 replaced with L-isoleucine 270 EQUAL L-arginine 271 replaced with L-proline 271 EQUAL L-valine 272 replaced with L-cysteine 272 EQUAL L-alanine 273 replaced with glycine 273 EQUAL L-valine 274 replaced with L-cysteine 274 EQUAL L-alanine 275 replaced with glycine 275 EQUAL L-alanine 276 replaced with L-cysteine 276 EQUAL glycine 277 replaced with L-tryptophan 277 EQUAL 22 EQUAL 277 EQUAL Reactome Database ID Release 78 9631888 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631888 Reactome Database ID Release 78 9036077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036077 Reactome R-HSA-9036077 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036077.2 Reactome Database ID Release 78 2206280 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206280 Reactome R-HSA-2206280 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206280.2 8793927 Pubmed 1996 Clinical and biochemical manifestations of hyaluronidase deficiency Natowicz, M R Short, M P Wang, Y Dickersin, G R Gebhardt, M C Rosenthal, D I Sims, K B Rosenberg, A E N. Engl. J. Med. 335:1029-33 Reactome Database ID Release 78 2206281 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2206281 Reactome R-HSA-2206281 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2206281.2 22013531 Pubmed 2012 Glycosaminoglycan storage disorders: a review Coutinho, MF Lacerda, L Alves, S Biochem Res Int 2012:471325 22210669 Pubmed 2011 Overview of the mucopolysaccharidoses Muenzer, J Rheumatology (Oxford) 50:v4-12 22210670 Pubmed 2011 Diagnosis of the mucopolysaccharidoses Lehman, Thomas J A Miller, Nicole Norquist, Becky Underhill, Lisa Keutzer, Joan Rheumatology (Oxford) 50:v41-8 0079130356 ISBN 2001 The Mucopolysaccharidoses Neufeld, Elizabeth F Muenzer, J The Metabolic and Molecular Bases of Inherited Disease, 8th ed (Book) 16414358 Pubmed 2006 Mucopolysaccharidoses and the eye Ashworth, Jane L Biswas, Susmito Wraith, Ed Lloyd, I Chris Surv Ophthalmol 51:1-17 19111581 Pubmed 2009 Lysosomal disorders: from storage to cellular damage Ballabio, A Gieselmann, V Biochim Biophys Acta 1793:684-96 Glycogen storage diseases Glycogen storage diseases The regulated turnover of glycogen plays a central, tissue-specific role in the maintenance of blood glucose levels and in the provision of glucose to tissues such as muscle and brain in response to stress. Defects in the enzymes involved in glycogen turnover are associated with abnormal responses to fasting and exercise that can differ widely in their presentation and severity. Additional symptoms can be the result of accumulation of abnormal products of glycogen metabolism (Hauk et al. 1959; Hers 1964; Shin 2006). Annotations are provided here for diseases due to deficiencies of GYS1 and GYS1 (glycogen synthase 1 and 2; glycogen storage disease type 0 (GSD type 0), of G6PC (glucose-6-phosphatase, GSD type Ia) and the SLC37A4 transporter (GSD type Ib), of GAA (lysosomal acid alpha-glucosidase, GSD type II), of GBE1 (glycogen branching enzyme, GSD type IV), and of GYG1 (glycogenin 1, GSD XV). Two additional diseases, myoclonic epilepsy of Lafora (Roach et al. 2012) and severe congenital neutropenia type 4 (Boztug et al. 2009), are included as they are due to defects in enzymes of glycogen metabolism. Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 Glycogen storage disease type 0 (muscle GYS1) Glycogen storage disease type 0 (muscle GYS1) GSD 0 (muscle) Glycogen synthase 1 (GYS1 "muscle") is widely expressed in the body. It normally catalyzes the addition of glucose residues to a growing glycogen molecule. In its absence, glycogen synthesis fails. This deficiency is most prominently associated with exercise intolerance and cardiomyopathy (Kolberg et al. 2007; Cameron et al. 2009). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 2.4.1.11 Defective GYS1 does not transfer glucose to growing glycogen chains Defective GYS1 does not transfer glucose to growing glycogen chains Glycogen synthase 1 (GYS1) normally catalyzes the addition of glucose residues to a growing glycogen molecule. In its absence, glycogen synthesis fails. GYS1 ("muscle") is widely expressed in the body and its deficiency is most prominently associated with exercise intolerance and cardiomyopathy (Kolberg et al. 2007; Cameron et al. 2009). Two human GYS1 mutations have been described. The one annotated here is a nonsense mutation (Kolberg et al. 2007); no glycogen is detectable in microscopic studies of skeletal and cardiac muscle from affected individuals. The other is a frame-shift mutation predicted to encode a truncated protein with an abnormal carboxy terminus (Cameron et al. 2009). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-08-17 Reactome DB_ID: 9628615 1 oligoGlc-GYG1:GYS1 R462* tetramer [cytosol] oligoGlc-GYG1:GYS1 R462* tetramer Reactome DB_ID: 29926 1 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI 18420 Reactome DB_ID: 70292 2 UniProt:P46976 GYG1 GYG1 GYG GYG1 FUNCTION Self-glucosylates, via an inter-subunit mechanism, to form an oligosaccharide primer that serves as substrate for glycogen synthase.ACTIVITY REGULATION Inhibited by palladium ions.PATHWAY Glycan biosynthesis; glycogen biosynthesis.SUBUNIT Homodimer (PubMed:22160680). Interacts (via C-terminus) with glycogen synthase GYS1 (PubMed:17055998). Interacts (via C-terminus) with glycogen synthase GYS2 (By similarity). This interaction is required for GYS2-mediated glycogen synthesis (By similarity).TISSUE SPECIFICITY Highly expressed in skeletal muscle and heart, with lower levels in brain, lung, kidney and pancreas.PTM Self-glycosylated by the transfer of glucose residues from UDP-glucose to itself, forming an alpha-1,4-glycan of around 10 residues attached to Tyr-195.PTM Phosphorylated.SIMILARITY Belongs to the glycosyltransferase 8 family. Glycogenin subfamily. UniProt P46976 O4'-glucosyl-L-tyrosine (alpha-D-glucosyl {alpha-D-glucosyl-(1->4)}n-alpha-D-glucopyranoside) at 195 195 EQUAL O4'-glucosyl-L-tyrosine [MOD:00166] ChEBI 28778 modification 2 EQUAL 350 EQUAL Reactome DB_ID: 3828056 2 UniProt:P13807 GYS1 GYS1 GYS GYS1 FUNCTION Transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.ACTIVITY REGULATION Allosteric activation by glucose-6-phosphate. Phosphorylation reduces the activity towards UDP-glucose. When in the non-phosphorylated state, glycogen synthase does not require glucose-6-phosphate as an allosteric activator; when phosphorylated it does (By similarity).PATHWAY Glycan biosynthesis; glycogen biosynthesis.SUBUNIT Interacts with GYG1.PTM Phosphorylation at Ser-8 by AMPK inactivates the enzyme activity. Primed phosphorylation at Ser-657 (site 5) by CSNK2A1 and CSNK2A2 is required for inhibitory phosphorylation at Ser-641 (site 3a), Ser-645 (site 3b), Ser-649 (site 3c) and Ser-653 (site 4) by GSK3A an GSK3B (By similarity). Phosphorylated at Ser-641 by DYRK2, leading to inactivation (By similarity). Phosphorylated at Ser-641 by PASK, leading to inactivation; phosphorylation by PASK is inhibited by glycogen. Dephosphorylation at Ser-641 and Ser-645 by PP1 activates the enzyme.SIMILARITY Belongs to the glycosyltransferase 3 family. UniProt P13807 2 EQUAL 461 EQUAL Reactome Database ID Release 78 9628615 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9628615 Reactome R-HSA-9628615 8 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9628615.8 Reactome DB_ID: 29410 8 UDP-D-glucose [ChEBI:18066] UDP-D-glucose ChEBI 18066 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9628615 GO 0004373 GO molecular function Reactome Database ID Release 78 9634039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9634039 Reactome Database ID Release 78 3828061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3828061 Reactome R-HSA-3828061 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3828061.5 17928598 Pubmed 2007 Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0 Kollberg, G Tulinius, M Gilljam, T Ostman-Smith, I Forsander, G Jotorp, P Oldfors, A Holme, E N Engl J Med 357:1507-14 19699667 Pubmed 2009 Identification of a novel mutation in GYS1 (muscle-specific glycogen synthase) resulting in sudden cardiac death, that is diagnosable from skin fibroblasts Cameron, JM Levandovskiy, V Mackay, Nevena Utgikar, Rucha Ackerley, Cameron A Chiasson, David Halliday, William Raiman, Julian Robinson, BH Mol. Genet. Metab. 98:378-82 Reactome Database ID Release 78 3828062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3828062 Reactome R-HSA-3828062 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3828062.3 Glycogen storage disease type 0 (liver GYS2) Glycogen storage disease type 0 (liver GYS2) GSD 0 Glycogen synthase 2 (GYS2 "liver") normally catalyzes the addition of glucose residues to a growing glycogen molecule. In its absence, glycogen synthesis fails. Expression of GYS2 is confined to the liver and its deficiency is most prominently associated with fasting hypoglycemia (Gitzelmann et al. 1996; Orho et al. 1998). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 2.4.1.11 Defective GYS2 does not transfer glucose to growing glycogen chains Defective GYS2 does not transfer glucose to growing glycogen chains Glycogen synthase 2 (GYS2) normally catalyzes the addition of glucose residues to a growing glycogen molecule. In its absence, glycogen synthesis fails. GYS2 is expressed in the liver and its deficiency is most prominently associated with fasting hypoglycemia (Gitzelmann et al. 1996). Seven human GYS2 mutations have been described, one frameshift and six missense mutations (Orho et al. 1998), Two of the missense mutations are annotated here. Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-08-17 Reactome DB_ID: 9628616 1 oligoGlc-GYG2:GYS2 mutant tetramer [cytosol] oligoGlc-GYG2:GYS2 mutant tetramer Reactome DB_ID: 29926 1 Converted from EntitySet in Reactome Reactome DB_ID: 3858509 2 GYS2 mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GYS2 H446D [cytosol] GYS2 N39S [cytosol] UniProt P54840 Reactome DB_ID: 70289 2 UniProt:O15488 GYG2 GYG2 GYG2 FUNCTION Self-glucosylates, via an inter-subunit mechanism, to form an oligosaccharide primer that serves as substrate for glycogen synthase.PATHWAY Glycan biosynthesis; glycogen biosynthesis.SUBUNIT Homodimer, tightly complexed to glycogen synthase.TISSUE SPECIFICITY Detected in liver (at protein level) (PubMed:9857012). Expressed preferentially in liver, heart, and pancreas (PubMed:9346895).PTM Self-glycosylated by the transfer of glucose residues from UDP-glucose to itself, forming an alpha-1,4-glycan of around 10 residues attached to Tyr-228.SIMILARITY Belongs to the glycosyltransferase 8 family. Glycogenin subfamily. UniProt O15488 O4'-glucosyl-L-tyrosine (alpha-D-glucosyl {alpha-D-glucosyl-(1->4)}n-alpha-D-glucopyranoside) at 228 228 EQUAL 1 EQUAL 501 EQUAL Reactome Database ID Release 78 9628616 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9628616 Reactome R-HSA-9628616 8 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9628616.8 Reactome DB_ID: 29410 8 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9628616 Reactome Database ID Release 78 9634041 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9634041 Reactome Database ID Release 78 3858506 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858506 Reactome R-HSA-3858506 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858506.4 9691087 Pubmed 1998 Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0 Orho, Marju Bosshard, Nils U Buist, NR Gitzelmann, Richard Aynsley-Green, A Blumel, P Gannon, MC Nuttall, FQ Groop, LC J Clin Invest 102:507-15 8831078 Pubmed 1996 Liver glycogen synthase deficiency: a rarely diagnosed entity Gitzelmann, Richard Spycher, M A Feil, G Müller, J Seilnacht, B Stahl, M Bosshard, Nils U Eur. J. Pediatr. 155:561-7 Reactome Database ID Release 78 3858516 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858516 Reactome R-HSA-3858516 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858516.2 Glycogen storage disease type Ia (G6PC) Glycogen storage disease type Ia (G6PC) GSD Ia Glucose-6-phosphatase (G6PC) associated with the inner face of the endoplasmic reticulum membrane normally catalyzes the hydrolysis of glucose-6-phosphate to glucose and orthophosphate. Defects in glucose-6-phosphatase are the cause of glycogen storage disease type Ia (Lei et al. 1993, 1995, Chou and Mansfield 2008). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 3.1.3.9 Defective G6PC does not hydrolyze glucose 6-phosphate Defective G6PC does not hydrolyze glucose 6-phosphate Glucose-6-phosphatase (G6PC) associated with the inner face of the endoplasmic reticulum membrane normally catalyzes the hydrolysis of glucose-6-phosphate to glucose and orthophosphate. Defects in glucose-6-phosphatase are the cause of glycogen storage disease type 1a. The three missense mutant forms of G6PC annotated here are examples of the many that have been described (Lei et al. 1993, 1995, Chou and Mansfield 2008). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-08-17 Reactome DB_ID: 113782 1 endoplasmic reticulum lumen GO 0005788 alpha-D-glucose 6-phosphate(2-) [ChEBI:58225] alpha-D-glucose 6-phosphate(2-) alpha-D-glucose 6-phosphate dianion alpha-D-glucopyranose 6-phosphate 6-O-phosphonato-alpha-D-glucopyranose alpha-D-glucose 6-phosphate ChEBI 58225 Reactome DB_ID: 113519 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3274535 endoplasmic reticulum membrane GO 0005789 G6PC mutants [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity G6PC R170Q [endoplasmic reticulum membrane] G6PC H119L [endoplasmic reticulum membrane] G6PC R83C [endoplasmic reticulum membrane] UniProt P35575 GO 0004346 GO molecular function Reactome Database ID Release 78 9631870 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631870 Reactome Database ID Release 78 3274540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3274540 Reactome R-HSA-3274540 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3274540.2 18449899 Pubmed 2008 Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease Chou, Janice Y Mansfield, Brian C Hum. Mutat. 29:921-30 8211187 Pubmed 1993 Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a Lei, K-J Shelly, Leslie L Pan, Chi-Jiunn Sidbury, James B Chou, Janice Y Science 262:580-3 Reactome Database ID Release 78 3274531 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3274531 Reactome R-HSA-3274531 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3274531.2 Glycogen storage disease type Ib (SLC37A4) Glycogen storage disease type Ib (SLC37A4) GSD Ib The SLC37A4 transport protein in the endoplasmic reticulum membrane normally mediates the exchange of cytosolic glucose-6-phosphate and orthophosphate from the endoplasmic reticulum lumen. Defects in this transporter are associated with glycogen storage disease type Ib (Gerin et al. 1997; Chen et al. 2008; Veiga-da-Cunha et al. 1998). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 Defective SLC37A4 does not exchange G6P and Pi across the ER membrane Defective SLC37A4 does not exchange G6P and Pi across the ER membrane The SLC37A4 transport protein in the endoplasmic reticulum membrane normally mediates the exchange of cytosolic glucose-6-phosphate and orthophosphate from the endoplasmic reticulum lumen. Defects in this transporter are associated with glycogen storage disease type Ib. The two missense mutant forms of SLC37A4 annotated here are examples of the many that have been described (Gerin et al. 1997; Chen et al. 2008; Veiga-da-Cunha et al. 1998). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-08-17 Reactome DB_ID: 113551 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 30537 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3229129 SLC37A4 mutants [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SLC37A4 G88D [endoplasmic reticulum membrane] SLC37A4 G20D [endoplasmic reticulum membrane] UniProt O43826 GO 0061513 GO molecular function Reactome Database ID Release 78 9631822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631822 Reactome Database ID Release 78 3229118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3229118 Reactome R-HSA-3229118 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3229118.2 18337460 Pubmed 2008 The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient in glycogen storage disease type Ib and Ic Chen, Shih-Yin Pan, Chi-Jiunn Nandigama, Krishnamachary Mansfield, Brian C Ambudkar, Suresh V Chou, Janice Y FASEB J. 22:2206-13 9428641 Pubmed 1997 Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib Gerin, I Veiga-da-Cunha, M Achouri, Y Collet, JF Van Schaftingen, Emile FEBS Lett 419:235-238 9758626 Pubmed 1998 A gene on chromosome 11q23 coding for a putative glucose- 6-phosphate translocase is mutated in glycogen-storage disease types Ib and Ic Veiga-da-Cunha, M Gerin, I Chen, Yuan-Tsong de Barsy, Thierry de Lonlay, Pascale Dionisi-Vici, C Fenske, Christiane D Lee, Philip J Leonard, JV Maire, I McConkie-Rosell, A Schweitzer, Susanne Vikkula, Miikka Van Schaftingen, Emile Am. J. Hum. Genet. 63:976-83 Reactome Database ID Release 78 3229133 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3229133 Reactome R-HSA-3229133 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3229133.2 Glycogen storage disease type II (GAA) Glycogen storage disease type II (GAA) GSD II Glycogen storage disease type II (GSD II - Pompe's disease) is caused by mutations that reduce or eliminate the activity of lysosomal alpha-glucosidase (GAA) (Hers 1963). The presentation of GSD II varies with the severity of the mutation: patients with little or no GAA activity are affected shortly after birth and multiple tissues are severely affected. Patients with higher levels of GAA activity present later in life, often with symptoms restricted tocardiac and skeletal muscle (Leslie & Tinkle). At a cellular level, symptoms of the disease are due to accumulation of structurally normal glycogen in lysosomes. Glycogen, thought to enter lysosomes via autophagy, is fully degraded by GAA (Brown et al. 1970), but accumulates if the enzyme is absent or reduced in activity.<p>The two mutant alleles annotated here are associated with near-complete loss of enzyme activity and early onset of disease (Hermans et al. 1991; Zhong et al. 1991). Many other mutant alleles have been described and their residual activities correlated with disease presentation (e.g., Kroos et al. 2012). Authored: D'Eustachio, Peter, 2014-03-24 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2014-03-24 3.2.1.20 Defective GAA does not hydrolyze lysosomal glycogen Defective GAA does not hydrolyze lysosomal glycogen Defective GAA does not hydrolyze alpha(1,6) linkages in lysosomal glycogen Defective GAA does not hydrolyze alpha(1,4) linkages in lysosomal glycogen Normally, lysosomal alpha-glucosidase (GAA) catalyzes the hydrolysis of alpha(1,4) and alpha(1,6) linkages in glycogen, yielding free glucose and shortened glycogen polymers. A wide variety of GAA mutations reduce or eliminate this catalytic activity, leading to glycogen accumulation in lysosomes. The two missense mutant alleles annotated here encode GAA variants with little or no activity and are associated with the infantile form of the disease (early onset with multiple tissues involved) (Brown et al. 1970; Hermans et al. 1991; Zhong et al. 1991). The defect primarily affects skeletal and cardiac muscle, so the disease event is annotated here as a failure of processing of the muscle (GYG1) form of glycogen. Authored: D'Eustachio, Peter, 2014-03-24 Reviewed: Jassal, Bijay, 2014-03-28 Edited: D'Eustachio, Peter, 2014-03-24 Reactome DB_ID: 9036726 1 glycogen-GYG1 dimer [lysosomal lumen] glycogen-GYG1 dimer Reactome DB_ID: 9036728 2 O4'-glucosyl-L-tyrosine (glycogen group) at 195 195 EQUAL ChEBI 28087 modification 2 EQUAL 350 EQUAL Reactome DB_ID: 5357557 1 manganese(2+) [ChEBI:29035] manganese(2+) manganese(II) manganous ion MANGANESE (II) ION manganese, ion (Mn2+) Mn(2+) ChEBI 29035 Reactome Database ID Release 78 9036726 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036726 Reactome R-HSA-9036726 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036726.1 Reactome DB_ID: 1605715 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5357599 GAA mutants [lysosomal lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GAA E521K [lysosomal lumen] GAA M318T [lysosomal lumen] UniProt P10253 GO 0090599 GO molecular function Reactome Database ID Release 78 9631935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631935 Reactome Database ID Release 78 9036729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9036729 Reactome R-HSA-9036729 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9036729.2 3049072 Pubmed 1988 Primary structure and processing of lysosomal alpha-glucosidase; homology with the intestinal sucrase-isomaltase complex Hoefsloot, Lies H Hoogeveen-Westerveld, Marianne Kroos, Marian A van Beeumen, Jos Reuser, Arnold J J Oostra, Ben A EMBO J. 7:1697-704 8420990 Pubmed 1993 Structural and functional changes of lysosomal acid alpha-glucosidase during intracellular transport and maturation Wisselaar, Heleen A Kroos, Marian A Hermans, Monique M P van Beeumen, Jos Reuser, Arnold J J J. Biol. Chem. 268:2223-31 5264799 Pubmed 1970 Simultaneous absence of alpha-1,4-glucosidase and alpha-1,6-glucosidase activities (pH 4) in tissues of children with type II glycogen storage disease Brown, Barbara Illingworth Brown, David H Jeffrey, Peter L Biochemistry 9:1423-8 Reactome Database ID Release 78 5357609 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5357609 Reactome R-HSA-5357609 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357609.3 1652892 Pubmed 1991 Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele Zhong, Nan Martiniuk, Frank Tzall, Stephanie Hirschhorn, Rochelle Am. J. Hum. Genet. 49:635-45 22644586 Pubmed 2012 Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants Kroos, Marian A Hoogeveen-Westerveld, Marianne Michelakakis, Helen Pomponio, Robert J Van der Ploeg, Ans T Halley, Dicky J Reuser, Arnold J J Hum. Mutat. 33:1161-5 1898413 Pubmed 1991 Identification of a point mutation in the human lysosomal alpha-glucosidase gene causing infantile glycogenosis type II Hermans, Monique M P de Graaff, Esther Kroos, Marian A Wisselaar, Heleen A Oostra, Ben A Reuser, Arnold J J Biochem. Biophys. Res. Commun. 179:919-26 http://www.ncbi.nlm.nih.gov/books/NBK1261/ Glycogen Storage Disease Type II (Pompe Disease) Leslie, Nancy Tinkle, Brad T 13954110 Pubmed 1963 alpha-Glucosidase deficiency in generalized glycogen-storage disease (Pompe's disease) Hers, Henri-Gery Biochem. J. 86:11-6 Glycogen storage disease type IV (GBE1) Glycogen storage disease type IV (GBE1) GSD IV Andersen Disease Normally, cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules transfers terminal alpha(1,4) glucose blocks to form alpha(1,6) branches on growing glycogen molecules of both liver and muscle types. In the absence of GBE1 activity, abnormal amylopectin-like glycogen with longer alpha(1,4) chains and fewer branch points forms in all tissues where glycogen is normally found. Presentation of the disease is clinically heterogeneous: missense and nonsense mutations associated with little or no enzyme activity can lead to progressive liver disease or neuromuscuolar disease (Bao et al. 1996; Bruno et al. 2004). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 2.4.1.18 Defective GBE1 does not catalyze branch formation in growing glycogen chains (liver) Defective GBE1 does not catalyze branch formation in growing glycogen chains (liver) Normally, cytosolic glycogen branching enzyme (GBE1) associated with glycogen granules transfers terminal alpha(1,4) glucose blocks to form alpha(1,6) branches on growing glycogen molecules of both liver and muscle types. In the absence of GBE1 activity, abnormal amylopectin-like glycogen with longer alpha(1,4) chains and fewer branch points forms in all tissues where glycogen is normally found. Presentation of the disease is clinically heterogeneous. The two missense mutant alleles annotated here, associated with near-complete loss of GBE1 activity, lead to progressive liver disease.A nonsense mutant allele R524X and a large internal deletion are also associated with this presentation, while a L224P missense mutation is associated with partial reduction of enzyme activity and nonprogressive liver disease (Bao et al. 1996) and other missense and nonsense mutations (e.g., H243R, R637X) are associated with absent enzyme activity and a neuromuscular disease presentation (Bruno et al. 2004). GBE1 deficiency is thus well-established as the molecular basis of GSD IV, but the basis of its variable presentation in children with little or no enzyme activity remains unclear. Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-08-17 Reactome DB_ID: 3322056 1 polyGlc-GYG2:GYS2-a tetramer [cytosol] polyGlc-GYG2:GYS2-a tetramer Reactome DB_ID: 29926 1 Reactome DB_ID: 71599 2 UniProt:P54840 GYS2 GYS2 GYS2 FUNCTION Transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.ACTIVITY REGULATION Allosteric activation by glucose-6-phosphate. Phosphorylation reduces the activity towards UDP-glucose. When in the non-phosphorylated state, glycogen synthase does not require glucose-6-phosphate as an allosteric activator; when phosphorylated it does (By similarity).PATHWAY Glycan biosynthesis; glycogen biosynthesis.SUBUNIT Interacts with GYG1 (via C-terminus); required for GYS2-mediated glycogen synthesis.PTM Primed phosphorylation at Ser-657 (site 5) by CSNK2A1 and CSNK2A2 is required for inhibitory phosphorylation at Ser-641 (site 3a), Ser-645 (site 3b), Ser-649 (site 3c) and Ser-653 (site 4) by GSK3A an GSK3B. Dephosphorylation at Ser-641 and Ser-645 by PP1 activates the enzyme (By similarity). Phosphorylation at Ser-8 is not required for interaction with GYG1 (By similarity). Interaction with GYG1 does not regulate the phosphorylation at Ser-8 and Ser-641 (By similarity).SIMILARITY Belongs to the glycosyltransferase 3 family. 1 EQUAL 703 EQUAL Reactome DB_ID: 70188 2 O4'-glucosyl-L-tyrosine ((1,4-alpha-D-glucosyl)n group) at 228 228 EQUAL ChEBI 15444 modification 1 EQUAL 501 EQUAL Reactome Database ID Release 78 3322056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3322056 Reactome R-HSA-3322056 8 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3322056.8 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3878772 GBE1 mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GBE1 R515C [cytosol] GBE1 F257L [cytosol] UniProt Q04446 GO 0003844 GO molecular function Reactome Database ID Release 78 9631892 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631892 Reactome Database ID Release 78 3878762 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3878762 Reactome R-HSA-3878762 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3878762.3 15452297 Pubmed 2004 Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV) Bruno, C van Diggelen, O P Cassandrini, D Gimpelev, M Giuffrè, B Donati, M A Introvini, P Alegria, A Assereto, S Morandi, L Mora, M Tonoli, E Mascelli, S Traverso, M Pasquini, E Bado, M Vilarinho, L van Noort, G Mosca, F DiMauro, S Zara, F Minetti, C Neurology 63:1053-8 8613547 Pubmed 1996 Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. Bao, Y Kishnani, Priya S Wu, Jer-Yuarn Chen, Yuan-Tsong J Clin Invest 97:941-8 Reactome Database ID Release 78 3878781 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3878781 Reactome R-HSA-3878781 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3878781.2 Glycogen storage disease type XV (GYG1) Glycogen storage disease type XV (GYG1) GSD XV Glycogen synthesis is normally initiated by the autoglycosylation of glycogenin (GYG) to form oligo (1,4)-alpha-D-glucosyl GYG. A missense mutation of GYG1 yields a protein that cannot undergo glucosylation, leading to failure of glycogen synthesis, associated with muscle weakness and other abnormalities (Moslemi et al. 2010). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 2.4.1.186 Defective GYG1 is not autoglucosyolated Defective GYG1 is not autoglucosyolated Muscle glycogen synthesis is normally initiated by the autoglycosylation of glycogenin 1 (GYG1) to form oligo (1,4)-alpha-D-glucosyl GYG1. A missense mutation of GYG1 yields a protein that cannot undergo glucosylation, leading to failure of glycogen synthesis, associated with muscle weakness and other abnormalities (Moslemi et al. 2010). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-08-17 Reactome DB_ID: 3322050 1 GYG1:GYS1-a tetramer [cytosol] GYG1:GYS1-a tetramer Reactome DB_ID: 29926 1 Reactome DB_ID: 70190 2 2 EQUAL 350 EQUAL Reactome DB_ID: 71565 2 2 EQUAL 737 EQUAL Reactome Database ID Release 78 3322050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3322050 Reactome R-HSA-3322050 8 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3322050.8 Reactome DB_ID: 29410 8 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9037663 mutant GYG1:GYS1-a tetramer [cytosol] mutant GYG1:GYS1-a tetramer Reactome DB_ID: 29926 1 Reactome DB_ID: 3814832 2 L-threonine 83 replaced with L-methionine 83 EQUAL L-threonine removal [MOD:01647] 2 EQUAL 350 EQUAL Reactome DB_ID: 71565 2 2 EQUAL 737 EQUAL Reactome Database ID Release 78 9037663 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9037663 Reactome R-HSA-9037663 8 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9037663.8 GO 0008466 GO molecular function Reactome Database ID Release 78 9631861 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631861 Reactome Database ID Release 78 3814838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3814838 Reactome R-HSA-3814838 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3814838.3 20357282 Pubmed 2010 Glycogenin-1 deficiency and inactivated priming of glycogen synthesis Moslemi, Ali-Reza Lindberg, Christopher Nilsson, Johanna Tajsharghi, Homa Andersson, Bert Oldfors, A N. Engl. J. Med. 362:1203-10 Reactome Database ID Release 78 3814836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3814836 Reactome R-HSA-3814836 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3814836.2 Myoclonic epilepsy of Lafora Myoclonic epilepsy of Lafora Lafora disease is a progressive neurodegenerative disorder with onset typically late in childhood, characterized by seizures and progressive neurological deterioration and death within ten years of onset. Recessive mutations in EPM2A (laforin) and NHLRC1 (malin) have been identified as causes of the disease. The disease is classified here as one of glycogen storage as EPM2A (laforin) and NHLRC1 (malin) regulate normal glycogen turnover and defects in either protein are associated with the formation of Lafora bodies, accumulations of abnormal, insoluble glycogen molecules in tissues including brain, muscle, liver, and heart (Ramachandran et al. 2009; Roach et al. 2012). Consistent with a central role for glycogen accumulation in the disease, reduced (Turnbull et al. 2011) or absent (Pederson et al. 2013) glycogen synthase activity prevents Lafora Disease in mouse models.<p>Type 2A disease. EPM2A (laforin) associated with cytosolic glycogen granules, normally catalyzes the removal of the phosphate groups added rarely but consistently to growing glycogen molecules (Tagliabracci et al. 2011). Defects in this catalytic activity lead to the formation of phosphorylated glycogen molecules that are insoluble and that show abnormal branching patterns (Minassian et al. 1998, Serratosa et al. 1999, Tagliabracci et al. 2011).<p>Type 2B disease. NHLRC1 (malin) normally mediates polyubiquitination of EPM2A (laforin) and PPP1R3C (PTG). The two polyubiquitinated proteins are targeted for proteasome-mediated degradation, leaving a glycogen-glycogenin particle associated with glycogen synthase. In the absence of NHLRC1 activity, EPM2A and PPP1R3C proteins appear to persist, associated with the formation of abnormal, stable glycogen granules (Lafora bodies) (Chan et al. 2003; Gentry et al. 2005). In NHLRC1 knockout mice PPP1R3C levels are unchanged rather than increased, suggesting that NHLRC1 does not target PPP1R3C for degradation. However, EPM2A protein levels are increased in this knockout consistent with NHLRC1's proposed role (DePaoli-Roach et al. 2010). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Pederson, Bart, 2014-02-18 Edited: D'Eustachio, P, 2013-07-19 Defective EPM2A does not dephosphorylate phosphoglycogen (type 2A disease) Defective EPM2A does not dephosphorylate phosphoglycogen (type 2A disease) EPM2A (laforin) associated with cytosolic liver- and muscle-form glycogen granules normally catalyzes the hydrolytic removal of the small numbers of phosphate groups incorporated into glycogen (Minassian et al. 1998, Serratosa et al. 1999, Tagliabracci et al. 2011). Defects in EMP2A (laforin) are the cause of the commonest form of Lafora disease. The three missense mutant forms of EPM2A (laforin) annotated here are examples of the disease-associated EPM2A alleles that have been described (Fernandez-Sanchez et al. 2003). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Pederson, Bart, 2014-02-18 Edited: D'Eustachio, Peter, 2014-05-19 Reactome DB_ID: 29356 1 Reactome DB_ID: 3780999 1 EPM2A:PPP1R3C:phosphoglycogen-GYG1:GYS1-a tetramer [cytosol] EPM2A:PPP1R3C:phosphoglycogen-GYG1:GYS1-a tetramer laforin:PTG:phosphoglycogen-GYG1:GYS1-a tetramer Reactome DB_ID: 29926 1 Reactome DB_ID: 3777102 1 UniProt:Q9UQK1 PPP1R3C PPP1R3C PPP1R3C PPP1R5 FUNCTION Acts as a glycogen-targeting subunit for PP1 and regulates its activity. Activates glycogen synthase, reduces glycogen phosphorylase activity and limits glycogen breakdown. Dramatically increases basal and insulin-stimulated glycogen synthesis upon overexpression in a variety of cell types.SUBUNIT Interacts with PPP1CC catalytic subunit of PP1 and associates with glycogen. Forms complexes with glycogen phosphorylase, glycogen synthase and phosphorylase kinase which is necessary for its regulation of PP1 activity. Also interacts with EPM2A/laforin.DOMAIN The N-terminal region is required for binding to PP1, the central region is required for binding to glycogen and the C-terminal region is required for binding to glycogen phosphorylase, glycogen synthase and phosphorylase kinase.PTM Ubiquitinated by NHLRC1/malin in a EPM2A/laforin-dependent manner. UniProt Q9UQK1 1 EQUAL 317 EQUAL Reactome DB_ID: 6805697 1 EPM2A dimer [cytosol] EPM2A dimer Reactome DB_ID: 3777103 2 UniProt:O95278 EPM2A EPM2A EPM2A FUNCTION Plays an important role in preventing glycogen hyperphosphorylation and the formation of insoluble aggregates, via its activity as glycogen phosphatase, and by promoting the ubiquitination of proteins involved in glycogen metabolism via its interaction with the E3 ubiquitin ligase NHLRC1/malin. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates (PubMed:16901901, PubMed:23922729, PubMed:26231210, PubMed:25538239, PubMed:25544560). Dephosphorylates phosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity with phosphoserine and phosphothreonine substrates (in vitro) (PubMed:11001928, PubMed:11220751, PubMed:11739371, PubMed:14532330, PubMed:16971387, PubMed:18617530, PubMed:22036712, PubMed:23922729, PubMed:14722920). Has been shown to dephosphorylate MAPT (By similarity). Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin (PubMed:23922729). Also promotes proteasome-independent protein degradation through the macroautophagy pathway (PubMed:20453062).SUBUNIT Homodimer (PubMed:16971387, PubMed:18617530, PubMed:23922729, PubMed:25538239, PubMed:25544560). Interacts with itself (PubMed:14532330). Interacts with PPP1R3B, PPP1R3C, PPP1R3D, HIRIP5, and EPM2AIP1 (PubMed:12782127, PubMed:12915448, PubMed:14532330, PubMed:16901901, PubMed:18070875). Binds glycogen and Lafora bodies (PubMed:11739371, PubMed:14532330, PubMed:14706656, PubMed:15102711, PubMed:18617530, PubMed:22036712). Interacts with NHLRC1/malin (via the NHL repeats) (PubMed:15930137, PubMed:22036712, PubMed:23922729). Forms a complex with NHLRC1/malin and HSP70 (PubMed:19036738). Interacts with PPP1R3D; in the presence of NHLC1/malin the interaction leads to ubiquitination and autophagic degradation of PPP1R3D. Interacts (via the phosphatase domain) with MAPT/Tau; the interaction dephosphorylates MAPT (PubMed:19542233). Isoform 1 and isoform 2 interact to form a heterodimeric complex that lacks phosphatase activity (in vitro) (PubMed:18617530). Active phosphatase isoform 7 and isoform 1 interact with each other, but give rise to lower phosphatase activity than isoform 1 or isoform 7 by themselves (in vitro) (PubMed:22036712). Active phosphatase isoform 7 and inactive isoform 2 interact with each other, but give rise to lower phosphatase activity than isoform 7 by itself (in vitro) (PubMed:22036712). Interacts with PRDM8 (PubMed:22961547).TISSUE SPECIFICITY Expressed in heart, skeletal muscle, kidney, pancreas and brain. Isoform 4 is also expressed in the placenta.DOMAIN The CBM20 domain mediates binding to cytoplasmic glycogen and to Lafora polyglucosan bodies.PTM Polyubiquitinated by NHLRC1/malin.PTM Phosphorylation on Ser-25 by AMPK affects the phosphatase activity of the enzyme and its ability to homodimerize and interact with NHLRC1, PPP1R3C or PRKAA2.SIMILARITY Belongs to the protein-tyrosine phosphatase family. UniProt O95278 1 EQUAL 331 EQUAL Reactome Database ID Release 78 6805697 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805697 Reactome R-HSA-6805697 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805697.1 Reactome DB_ID: 71565 2 2 EQUAL 737 EQUAL Reactome DB_ID: 3777092 2 O4'-glucosyl-L-tyrosine (polysaccharide phosphate group) at 195 195 EQUAL ChEBI 37639 modification 2 EQUAL 350 EQUAL Reactome Database ID Release 78 3780999 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3780999 Reactome R-HSA-3780999 9 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3780999.9 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9037665 mutant EPM2A:PPP1R3C:phosphoglycogen-GYG1:GYS1-a tetramer [cytosol] mutant EPM2A:PPP1R3C:phosphoglycogen-GYG1:GYS1-a tetramer mutant laforin:PTG:phosphoglycogen-GYG1:GYS1-a tetramer Reactome DB_ID: 29926 1 Reactome DB_ID: 3777102 1 1 EQUAL 317 EQUAL Reactome DB_ID: 71565 2 2 EQUAL 737 EQUAL Reactome DB_ID: 9037666 1 EPM2A mutant dimer [cytosol] EPM2A mutant dimer Converted from EntitySet in Reactome Reactome DB_ID: 3791352 2 EPM2A mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity EPM2A P301L [cytosol] EPM2A T194I [cytosol] EPM2A F84L [cytosol] Reactome Database ID Release 78 9037666 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9037666 Reactome R-HSA-9037666 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9037666.1 Reactome DB_ID: 3777092 2 O4'-glucosyl-L-tyrosine (polysaccharide phosphate group) at 195 195 EQUAL 2 EQUAL 350 EQUAL Reactome Database ID Release 78 9037665 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9037665 Reactome R-HSA-9037665 8 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9037665.8 GO 0019203 GO molecular function Reactome Database ID Release 78 9631938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631938 Reactome Database ID Release 78 3791349 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3791349 Reactome R-HSA-3791349 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3791349.3 14532330 Pubmed 2003 Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation Fernández-Sánchez, Maria Elena Criado-García, Olga Heath, Karen E García-Fojeda, Belén Medraño-Fernández, Iria Gómez-Garre, Pilar Sanz, Pascual Serratosa, Jose M Rodríguez de Córdoba, Santiago Hum. Mol. Genet. 12:3161-71 9931343 Pubmed 1999 A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2) Serratosa, Jose M Gómez-Garre, Pilar Gallardo, M Esther Anta, Berta de Bernabé, Daniel Beltran-Valero Lindhout, Dick Augustijn, Paul B Tassinari, Carlo A Michelucci, Roberto Malafosse, Alain Topcu, Meral Grid, Djamel Dravet, Charlotte Berkovic, Samuel F de Córdoba, Santiago Rodríguez Hum. Mol. Genet. 8:345-52 9771710 Pubmed 1998 Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy Minassian, Berge A Lee, Jeffrey R Herbrick, Jo-Anne Huizenga, Jack Soder, Sylvia Mungall, Andrew J Dunham, Ian Gardner, Rebecca Fong, Chung-yan G Carpenter, Stirling Jardim, L Satishchandra, P Andermann, Eva Snead, O Carter Lopes-Cendes, Iscia Tsui, LC Delgado-Escueta, Antonio V Rouleau, Guy A Scherer, Stephen W Nat. Genet. 20:171-4 21356517 Pubmed 2011 Phosphate incorporation during glycogen synthesis and Lafora disease Tagliabracci, Vincent S Heiss, Christian Karthik, Chandra Contreras, Christopher J Glushka, John Ishihara, Mayumi Azadi, Parastoo Hurley, Thomas D DePaoli-Roach, Anna A Roach, Peter J Cell Metab. 13:274-82 6.3.2.19 Defective NHLRC1 does not ubiquitinate EPM2A (laforin) and PPP1R3C (PTG) (type 2B disease) Defective NHLRC1 does not ubiquitinate EPM2A (laforin) and PPP1R3C (PTG) (type 2B disease) NHLRC1 (malin) mediates the ubiquitination of EPM2A (laforin) and PPP1R3C (PTG) associated with cytosolic liver- and muscle-form glycogen granules (Gentry et al. 2005). Defects in NHLRC1 (malin) are the cause of the second commonest form of Lafora disease (Roma-Mateo et al. 2012). The two missense mutant forms of NHLRC1 (malin) annotated here are examples of the disease-associated NHLRC1 alleles that have been described (Chan et al. 2003). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Pederson, Bart, 2014-02-18 Edited: D'Eustachio, Peter, 2014-05-19 Reactome DB_ID: 3781000 1 EPM2A:PPP1R3C:glycogen-GYG1:GYS1-a tetramer [cytosol] EPM2A:PPP1R3C:glycogen-GYG1:GYS1-a tetramer laforin:PTG:glycogen-GYG1:GYS1-a tetramer Reactome DB_ID: 29926 1 Reactome DB_ID: 3777102 1 1 EQUAL 317 EQUAL Reactome DB_ID: 6805697 1 Reactome DB_ID: 71565 2 2 EQUAL 737 EQUAL Reactome DB_ID: 70174 2 O4'-glucosyl-L-tyrosine (glycogen group) at 195 195 EQUAL 2 EQUAL 350 EQUAL Reactome Database ID Release 78 3781000 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3781000 Reactome R-HSA-3781000 9 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3781000.9 Converted from EntitySet in Reactome Reactome DB_ID: 113595 2 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBC(153-228) [cytosol] UBC(77-152) [cytosol] UBC(305-380) [cytosol] UBA52(1-76) [cytosol] RPS27A(1-76) [cytosol] UBB(77-152) [cytosol] UBC(609-684) [cytosol] UBC(533-608) [cytosol] UBC(229-304) [cytosol] UBC(457-532) [cytosol] UBC(1-76) [cytosol] UBB(1-76) [cytosol] UBC(381-456) [cytosol] UBB(153-228) [cytosol] UniProt P0CG48 UniProt P62987 UniProt P62979 UniProt P0CG47 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3797212 NHLRC1 mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NHLRC1 F33S [cytosol] NHLRC1 C26S [cytosol] UniProt Q6VVB1 GO 0004842 GO molecular function Reactome Database ID Release 78 9631903 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631903 Reactome Database ID Release 78 3797226 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3797226 Reactome R-HSA-3797226 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3797226.4 12958597 Pubmed 2003 Mutations in NHLRC1 cause progressive myoclonus epilepsy Chan, Elayne M Young, Edwin J Ianzano, Leonarda Munteanu, Iulia Zhao, Xiaochu Christopoulos, Constantine C Avanzini, Giuliano Elia, Maurizio Ackerley, Cameron A Jovic, Nebojsa J Bohlega, Saeed Andermann, Eva Rouleau, Guy A Delgado-Escueta, Antonio V Minassian, Berge A Scherer, SW Nat. Genet. 35:125-7 15930137 Pubmed 2005 Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin Gentry, Matthew S Worby, Carolyn A Dixon, JE Proc. Natl. Acad. Sci. U.S.A. 102:8501-6 22815132 Pubmed 2012 Deciphering the role of malin in the lafora progressive myoclonus epilepsy Romá-Mateo, Carlos Sanz, Pascual Gentry, Matthew S IUBMB Life 64:801-8 Reactome Database ID Release 78 3785653 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3785653 Reactome R-HSA-3785653 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3785653.3 20538597 Pubmed 2010 Genetic depletion of the malin E3 ubiquitin ligase in mice leads to lafora bodies and the accumulation of insoluble laforin DePaoli-Roach, Anna A Tagliabracci, Vincent S Segvich, Dyann M Meyer, Catalina M Irimia, Jose M Roach, Peter J J. Biol. Chem. 285:25372-81 22248338 Pubmed 2012 Glycogen and its metabolism: some new developments and old themes Roach, Peter J DePaoli-Roach, Anna A Hurley, Thomas D Tagliabracci, Vincent S Biochem. J. 441:763-87 23913475 Pubmed 2013 Inhibiting glycogen synthesis prevents lafora disease in a mouse model Pederson, Bart Turnbull, Julie Epp, Jonathan R Weaver, Staci A Zhao, Xiaochu Pencea, Nela Roach, Peter J Frankland, Paul Ackerley, Cameron A Minassian, Berge A Ann. Neurol. 19469843 Pubmed 2009 The autosomal recessively inherited progressive myoclonus epilepsies and their genes Ramachandran, Nivetha Girard, Jean-Marie Turnbull, Julie Minassian, Berge A Epilepsia 50:29-36 21552327 Pubmed 2011 PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease Turnbull, Julie DePaoli-Roach, Anna A Zhao, Xiaochu Cortez, Miguel A Pencea, Nela Tiberia, Erica Piliguian, Mark Roach, Peter J Wang, Peixiang Ackerley, Cameron A Minassian, Berge A PLoS Genet. 7:e1002037 Severe congenital neutropenia type 4 (G6PC3) Severe congenital neutropenia type 4 (G6PC3) SCN4 Glucose-6-phosphatase 3 (G6PC3) associated with the endoplasmic reticulum membrane normally catalyzes the hydrolysis of glucose-6-phosphate to glucose and orthophosphate. In the body, this enzyme is ubiquitously expressed; mutations that inactivate it are associated with severe congenital neutropenia (but not with fasting hypoglycemia or lactic acidemia) (Boztug et al. 2009, 2012). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, P, 2013-07-19 3.1.3.9 Defective G6PC3 does not hydrolyze glucose 6-phosphate Defective G6PC3 does not hydrolyze glucose 6-phosphate Glucose-6-phosphatase 3 (G6PC3) associated with the endoplasmic reticulum membrane normally catalyzes the hydrolysis of glucose-6-phosphate to glucose and orthophosphate. In the body, this enzyme is ubiquitously expressed; mutations that inactivate it are associated with severe congenital neutropenia (but not with fasting hypoglycemia or lactic acidemia) (Boztug et al. 2009, 2012). Authored: D'Eustachio, P, 2013-07-19 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-08-17 Reactome DB_ID: 113782 1 Reactome DB_ID: 113519 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3282874 G6PC3 mutants [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity G6PC3 R253H [endoplasmic reticulum membrane] G6PC3 G260R [endoplasmic reticulum membrane] UniProt Q9BUM1 Reactome Database ID Release 78 9631882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631882 Reactome Database ID Release 78 3282876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3282876 Reactome R-HSA-3282876 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3282876.2 19118303 Pubmed 2009 A syndrome with congenital neutropenia and mutations in G6PC3 Boztug, Kaan Appaswamy, Giridharan Ashikov, Angel Schäffer, Alejandro A Salzer, Ulrich Diestelhorst, Jana Germeshausen, Manuela Brandes, Gudrun Lee-Gossler, Jacqueline Noyan, Fatih Gatzke, Anna-Katherina Minkov, Milen Greil, Johann Kratz, Christian Petropoulou, Theoni Pellier, Isabelle Bellanné-Chantelot, Christine Rezaei, Nima Mönkemöller, Kirsten Irani-Hakimeh, Noha Bakker, Hans Gerardy-Schahn, Rita Zeidler, Cornelia Grimbacher, Bodo Welte, Karl Klein, Christoph N. Engl. J. Med. 360:32-43 22050868 Pubmed 2012 Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: novel genotypes and phenotypic variability in severe congenital neutropenia Boztug, Kaan Rosenberg, Philip S Dorda, Marie Banka, Siddharth Moulton, Thomas Curtin, Julie Rezaei, Nima Corns, John Innis, Jeffrey W Avci, Zekai Tran, Hung Chi Pellier, Isabelle Pierani, Paolo Fruge, Rachel Parvaneh, Nima Mamishi, Setareh Mody, Rajen Darbyshire, Phil Motwani, Jayashree Murray, Jennie Buchanan, GR Newman, William G Alter, Blanche P Boxer, Laurence A Donadieu, Jean Welte, Karl Klein, Christoph J. Pediatr. 160:679-683.e2 Reactome Database ID Release 78 3282872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3282872 Reactome R-HSA-3282872 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3282872.2 Reactome Database ID Release 78 3229121 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3229121 Reactome R-HSA-3229121 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3229121.2 14171618 Pubmed 1964 Glycogen storage disease Hers, Henri-Gery Adv Metab Disord 13:1-44 17027861 Pubmed 2006 Glycogen storage disease: clinical, biochemical, and molecular heterogeneity Shin, YS Semin Pediatr Neurol 13:115-20 13670930 Pubmed 1959 Enzymes of glycogen synthesis in glycogen-deposition disease Hauk, Rosalind Illingworth, Barbara Brown, David H Cori, Carl F Biochim. Biophys. Acta 33:554-6 Hereditary fructose intolerance Hereditary fructose intolerance Deficiencies in aldolase B arising from mutations in the aldolase B gene (ALDOB) prevent the cleavage of fructose 1-phosphate to glyceraldehyde (GA) and dihydroxyacetone phosphate (DHAP), leading to hereditary fructose intolerance (HFI). This autosomal recessive disorder is potentially fatal, but can be managed by exclusion of fructose from the diet (Cox et al. 1988; Tolan 1995). Authored: D'Eustachio, Peter, 2015-01-29 Reviewed: Timson, David J, Tolan, Dean R, 2015-02-16 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-01-29 Defective ALDOB does not cleave Fru 1-P to GA and DHAP Defective ALDOB does not cleave Fru 1-P to GA and DHAP Mutations in ALDOB that cause deficiency of aldolase B block the cleavage of fructose 1-phosphate (Fru 1-P) to glyceraldehyde (GA) and dihydroxyacetone phosphate (DHAP) and cause hereditary fructose intolerance (HFI). The links between the enzyme deficiency and pathology are unclear at present, but may involve depletion of the cellular phosphate pool and increased levels of Fru 1-P (Oberhaensli et al, 1987; Bouteldja & Timson, 2010). Affected individuals can develop severe hypoglycemia, lactic acidosis, and other metabolic abnormalities when fed fructose; the disease can be effectively managed by complete exclusion of fructose from the diet. A large number of ALDOB variants have been described in affected individuals (e.g. Tolan 1995); the two missense mutant alleles annotated here are the most common (53% of those with HFI have one of these alleles) (Cross et al. 1988; Cross et al. 1990; Coffee et al. 2010), and encode full length aldolase B proteins whose catalytic activity is sharply reduced due to considerable loss of stability (Malay et al., 2002; Malay et al. 2005; Rellos et al., 2000 - see also PDB structures 1XDL and 1XDM). Other less common variants, not annotated here, retain activities and thermal stabilities similar to the wild-type (Esposito et al, 2010). The physiological role of aldolase B has been established from metabolic and DNA sequencing studies of patients with HFI (Ali et al. 1998) and in a mouse model for this disease (Oppelt et al. 2015). Authored: D'Eustachio, Peter, 2015-01-29 Reviewed: Timson, David J, Tolan, Dean R, 2015-02-16 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-01-29 Reactome DB_ID: 31221 1 keto-D-fructose 1-phosphate [ChEBI:18105] keto-D-fructose 1-phosphate ChEBI 18105 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5656450 ALDOB mutant proteins [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0061609 GO molecular function Reactome Database ID Release 78 9631907 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631907 Reactome Database ID Release 78 5656438 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5656438 Reactome R-HSA-5656438 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5656438.3 3383242 Pubmed 1988 Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation Cross, Nicholas C P Tolan, Dean R Cox, Timothy M Cell 53:881-5 12464284 Pubmed 2002 The temperature dependence of activity and structure for the most prevalent mutant aldolase B associated with hereditary fructose intolerance Malay, Ali D Procious, Sheri L Tolan, Dean R Arch. Biochem. Biophys. 408:295-304 9610797 Pubmed 1998 Hereditary fructose intolerance Ali, Manir Rellos, Peter Cox, Timothy M J. Med. Genet. 35:353-65 2889861 Pubmed 1987 Study of hereditary fructose intolerance by use of 31P magnetic resonance spectroscopy Oberhaensli, Rolf D Rajagopalan, Bheeshma Taylor, Doris J Radda, George K Collins, Jane E Leonard, James V Schwarz, Hanspeter Herschkowitz, Norbert Lancet 2:931-4 8535439 Pubmed 1995 Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene Tolan, Dean R Hum Mutat 6:210-8 1967768 Pubmed 1990 Molecular analysis of aldolase B genes in hereditary fructose intolerance Cross, Nicholas C P de Franchis, Raffaella Sebastio, Gianfranco Dazzo, Caroline Tolan, Dean R Gregori, Claudine Odièvre, Michel Vidailhet, Michel Romano, Valentino Mascali, Gaetano Romano, Corrado Musumeci, Salvatore Steinmann, Beat Gitzelmann, Richard Cox, Timothy M Lancet 335:306-9 25637246 Pubmed 2015 Aldolase-B knockout in mice phenocopies hereditary fructose intolerance in humans Oppelt, Sarah A Sennott, Erin M Tolan, Dean R Mol. Genet. Metab. 20848650 Pubmed 2010 Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion Esposito, Gabriella Imperato, Maria Rosaria Ieno, Luigi Sorvillo, Rosa Benigno, Vincenzo Parenti, Giancarlo Parini, Rossella Vitagliano, Luigi Zagari, Adriana Salvatore, Francesco Hum. Mutat. 31:1294-303 10625657 Pubmed 2000 Expression, purification, and characterization of natural mutants of human aldolase B. Role of quaternary structure in catalysis Rellos, Peter Sygusch, Jurgen Cox, Timothy M J. Biol. Chem. 275:1145-51 20033295 Pubmed 2010 Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population Coffee, Erin M Yerkes, Laura Ewen, Elizabeth P Zee, Tiffany Tolan, Dean R J. Inherit. Metab. Dis. 33:33-42 15733923 Pubmed 2005 Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance Malay, Ali D Allen, Karen N Tolan, Dean R J. Mol. Biol. 347:135-44 Reactome Database ID Release 78 5657560 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5657560 Reactome R-HSA-5657560 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5657560.3 Essential fructosuria Essential fructosuria Deficiencies in KHK (ketohexokinase) are associated with essential fructosuria (Bonthron et al. 1994). Authored: D'Eustachio, Peter, 2015-01-29 Reviewed: Timson, David J, Tolan, Dean R, 2015-02-16 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-01-29 2.7.1.3 Defective KHK does not phosphorylate beta-D-fructose Defective KHK does not phosphorylate beta-D-fructose Variant KHK (ketohexokinase) protein fails to catalyze the phosphorylation of fructose to yield fructose 1-phosphate (Fru 1-P), the first step of fructose catabolism in the liver. This defect is associated with essential fructosuria, a rare benign condition characterized by elevated urinary fructose levels associated with consumption of fructose. Two missense mutant alleles have been identified in DNA sequencing studies of affected individuals (Bouthron et al. 1994). One, G40R, has no detectable activity. The second, A43T, encodes a protein whose liver ("A") isoform is inactive but whose peripheral ("C") isoform, though thermally unstable, retains some activity (Asipu et al. 2003). Authored: D'Eustachio, Peter, 2015-01-29 Reviewed: Timson, David J, Tolan, Dean R, 2015-02-16 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-01-29 Reactome DB_ID: 29532 1 D-fructose [ChEBI:15824] D-fructose ChEBI 15824 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5656460 KHK mutant dimers [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004454 GO molecular function Reactome Database ID Release 78 9631854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631854 Reactome Database ID Release 78 5656459 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5656459 Reactome R-HSA-5656459 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5656459.2 12941785 Pubmed 2003 Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria Asipu, Aruna Hayward, Bruce E O'Reilly, John Bonthron, David T Diabetes 52:2426-32 7833921 Pubmed 1994 Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase) Bonthron, David T Brady, Nicola Donaldson, Iain A Steinmann, Beat Hum Mol Genet 3:1627-31 Reactome Database ID Release 78 5657562 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5657562 Reactome R-HSA-5657562 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5657562.3 Essential pentosuria Essential pentosuria Essential pentosuria, the excretion in the urine of high levels of L-xylulose, is a benign autosomal recessive trait found in Ashkenazi Jewish and Lebanese populations. It is due to mutations that inactivate DXCR (L-xylulose reductase) and thus prevent the conversion of L-xylulose to xylitol in the glucuronate pathway (Pierce et al. 2011; Wang & van Eys 1970). Authored: D'Eustachio, Peter, 2015-02-25 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-02-25 1.1.1.10 Defective DCXR does not reduce L-xylulose to xylitol Defective DCXR does not reduce L-xylulose to xylitol Mutations that inactivate DCXR block the conversion of L-xylulose to xylitol. The two mutant alleles that have been characterized by DNA sequencing would encode truncated mRNAs and encode no detectable protein product. One of these mutant alleles, DCXR c.583?C, is annotated here (Pierce et al. 2011; Wang & van Eys 1970). Authored: D'Eustachio, Peter, 2015-02-25 Reviewed: Jassal, Bijay, 2015-08-17 Edited: D'Eustachio, Peter, 2015-02-25 Reactome DB_ID: 70106 1 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 5660036 1 L-xylulose [ChEBI:17399] L-xylulose ChEBI 17399 Reactome DB_ID: 29364 1 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion ChEBI 57783 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5662854 plasma membrane GO 0005886 UniProt:Q7Z4W1 DCXR DCXR SDR20C1 DCXR FUNCTION Catalyzes the NADPH-dependent reduction of several pentoses, tetroses, trioses, alpha-dicarbonyl compounds and L-xylulose. Participates in the uronate cycle of glucose metabolism. May play a role in the water absorption and cellular osmoregulation in the proximal renal tubules by producing xylitol, an osmolyte, thereby preventing osmolytic stress from occurring in the renal tubules.SUBUNIT Homotetramer.TISSUE SPECIFICITY Highly expressed in kidney, liver and epididymis. In the epididymis, it is mainly expressed in the proximal and distal sections of the corpus region. Weakly or not expressed in brain, lung, heart, spleen and testis.SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. UniProt Q7Z4W1 Replacement of residues 195 to 201 by TRPRLC 1 EQUAL 200 EQUAL GO 0050038 GO molecular function Reactome Database ID Release 78 9631949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631949 Reactome Database ID Release 78 5662851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5662851 Reactome R-HSA-5662851 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5662851.2 4392213 Pubmed 1970 The enzymatic defect in essential pentosuria Wang, Y M Van Eys, J N. Engl. J. Med. 282:892-6 22042873 Pubmed 2011 Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria Pierce, Sarah B Spurrell, Cailyn H Mandell, Jessica B Lee, Ming K Zeligson, Sharon Bereman, Michael S Stray, Sunday M Fokstuen, Siv Maccoss, MJ Levy-Lahad, Ephrat King, Mary-Claire Motulsky, Arno G Proc. Natl. Acad. Sci. U.S.A. 108:18313-7 Reactome Database ID Release 78 5662853 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5662853 Reactome R-HSA-5662853 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5662853.2 Pentose phosphate pathway disease Pentose phosphate pathway disease Mutant forms of two enzymes of the pentose phosphate pathway have been associated with disease in humans. A mutation in ribose-5-phosphate isomerase (RPIA), which normally mediates the reversible interconversion of D-ribulose-5-phosphate and ribose-5-phosphate, has been associated with a slowly progressive leukoencephalopathy, and mutations in transaldolase 1 (TALDO1), which normally mediates the reversible interconversion of D-fructose 6-phosphate and D-erythrose-4-phosphate to form sedoheptulose-7-phosphate and D-glyceraldehyde-3-phosphate, have been associated with congenital liver disease (Wamelink et al. 2008). Authored: D'Eustachio, Peter, 2015-02-24 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-02-24 RPIA deficiency: failed conversion of RU5P to R5P RPIA deficiency: failed conversion of RU5P to R5P A mutation in ribose-5-phosphate isomerase (RPIA), an enzyme of the pentose phosphate pathway that normally mediates the reversible interconversion of D-ribulose 5-phosphate and ribose 5-phosphate, has been associated with a slowly progressive leukoencephalopathy (Wamelink et al. 2008). Authored: D'Eustachio, Peter, 2015-02-24 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-02-24 5.3.1.6 Defective RPIA does not isomerize RU5P to R5P Defective RPIA does not isomerize RU5P to R5P A missense mutant form of RPIA (ribose 5-phosphate isomerase) fails to catalyze the reversible isomerization of ribulose 5-phosphate (RU5P) to ribose 5-phosphate (R5P). This enzyme defect was associated with a slowly progressive leukencephalopathy in the one patient who has been studied (Huck et al. 2004). Authored: D'Eustachio, Peter, 2015-02-24 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-02-24 Reactome DB_ID: 29732 1 D-ribulose 5-phosphate [ChEBI:17363] D-ribulose 5-phosphate ChEBI 17363 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5660009 UniProt:P49247 RPIA RPIA RPIA RPI PATHWAY Carbohydrate degradation; pentose phosphate pathway; D-ribose 5-phosphate from D-ribulose 5-phosphate (non-oxidative stage): step 1/1.SIMILARITY Belongs to the ribose 5-phosphate isomerase family. UniProt P49247 L-alanine 61 replaced with L-valine 61 EQUAL 1 EQUAL 311 EQUAL GO 0004751 GO molecular function Reactome Database ID Release 78 9631939 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631939 Reactome Database ID Release 78 5660013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5660013 Reactome R-HSA-5660013 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5660013.2 14988808 Pubmed 2004 Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy Huck, Jojanneke H J Verhoeven, Nanda M Struys, Eduard A Salomons, Gajja S Jakobs, Cornelis van der Knaap, Marjo S Am J Hum Genet 74:745-51 Reactome Database ID Release 78 6791461 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6791461 Reactome R-HSA-6791461 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6791461.2 18987987 Pubmed 2008 The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review Wamelink, Mirjam M C Struys, Eduard A Jakobs, Cornelis J Inherit Metab Dis 31:703-17 RPIA deficiency: failed conversion of R5P to RU5P RPIA deficiency: failed conversion of R5P to RU5P A mutation in ribose-5-phosphate isomerase (RPIA), an enzyme of the pentose phosphate pathway that normally mediates the reversible interconversion of ribose 5-phosphate and D-ribulose 5-phosphate, has been associated with a slowly progressive leukoencephalopathy (Wamelink et al. 2008). Authored: D'Eustachio, Peter, 2015-02-24 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-02-24 5.3.1.6 Defective RPIA does not isomerize R5P to RU5P Defective RPIA does not isomerize R5P to RU5P A missense mutant form of RPIA (ribose 5-phosphate isomerase) fails to catalyze the reversible isomerization of ribose 5-phosphate (R5P) to ribulose 5-phosphate (RU5P). This enzyme defect was associated with a slowly progressive leukencephalopathy in the one patient who has been studied (Huck et al. 2004). Authored: D'Eustachio, Peter, 2015-02-24 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-02-24 Reactome DB_ID: 73578 1 D-ribofuranose 5-phosphate(2-) [ChEBI:78346] D-ribofuranose 5-phosphate(2-) D-ribose 5-phosphate 5-O-phosphonato-D-ribofuranose ChEBI 78346 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5660009 L-alanine 61 replaced with L-valine 61 EQUAL 1 EQUAL 311 EQUAL Reactome Database ID Release 78 5660015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5660015 Reactome R-HSA-5660015 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5660015.2 Reactome Database ID Release 78 5659996 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659996 Reactome R-HSA-5659996 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659996.2 TALDO1 deficiency: failed conversion of Fru(6)P, E4P to SH7P, GA3P TALDO1 deficiency: failed conversion of Fru(6)P, E4P to SH7P, GA3P Mutations in transaldolase 1 (TALDO1), an enzyme of the pentose phosphate pathway that normally mediates the reversible interconversion of D-fructose 6-phosphate and D-erythrose 4-phosphate to form sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate, have been associated with congenital liver disease (Wamelink et al. 2008). Authored: D'Eustachio, Peter, 2015-08-18 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-08-18 2.2.1.2 Defective TALDO1 does not transform Fru(6)P, E4P to SH7P, GA3P Defective TALDO1 does not transform Fru(6)P, E4P to SH7P, GA3P Defective TALDO1 (transaldolase 1) fails to transform fructose 6-phosphate (Fru(6)P) and erythrose 4-phosphate (E4P) to sedoheptulose 7-phosphate (SH7P) and glyceraldehyde 3-phosphate (GA3P). This defect has been associated with congenital liver disease and an array of other symptoms. The deficiency was first described by Verhoeven and colleagues (2001). Both the range and severity of these abnormalities are variable from patient to patient (Wamelink et al. 2008a; Eyaid et al. 2013). The three missense mutant alleles annotated here are associated with absence of detectable transaldolase activity in tissues from homozygous affected individuals (LeDuc et al. 2014; Verhoeven et al. 2005; Wamelink et al. 2008b). Authored: D'Eustachio, Peter, 2015-08-18 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-08-18 Reactome DB_ID: 29512 1 beta-D-fructofuranose 6-phosphate(2-) [ChEBI:57634] beta-D-fructofuranose 6-phosphate(2-) 6-O-phosphonato-beta-D-fructofuranose beta-D-fructofuranose 6-phosphate dianion ChEBI 57634 Reactome DB_ID: 29878 1 D-erythrose 4-phosphate(2-) [ChEBI:16897] D-erythrose 4-phosphate(2-) ChEBI 16897 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5660002 TALDO1 mutant dimers [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004801 GO molecular function Reactome Database ID Release 78 9631785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631785 Reactome Database ID Release 78 5659998 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659998 Reactome R-HSA-5659998 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659998.2 23315216 Pubmed 2013 Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype Eyaid, Wafaa Al Harbi, Talal Anazi, Shamsa Wamelink, Mirjam M C Jakobs, Cornelis Al Salammah, Mohammad Al Balwi, Mohammed Alfadhel, Majid Alkuraya, Fowzan S J. Inherit. Metab. Dis. 36:997-1004 15877206 Pubmed 2005 A newborn with severe liver failure, cardiomyopathy and transaldolase deficiency Verhoeven, Nanda M Wallot, M Huck, Jojanneke H J Dirsch, O Ballauf, A Neudorf, U Salomons, Gajja S van der Knaap, Marjo S Voit, T Jakobs, Cornelis J. Inherit. Metab. Dis. 28:169-79 11283793 Pubmed 2001 Transaldolase deficiency: liver cirrhosis associated with a new inborn error in the pentose phosphate pathway. Verhoeven, Nanda M Huck, Jojanneke H J Roos, Birthe Struys, Eduard A Salomons, Gajja S Douwes, Adriaan C van der Knaap, Marjo S Jakobs, Cornelis Am J Hum Genet 68:1086-92 18331807 Pubmed 2008 Transaldolase deficiency in a two-year-old boy with cirrhosis Wamelink, Mirjam M C Struys, Eduard A Salomons, Gajja S Fowler, Darren Jakobs, Cornelis Clayton, Peter T Mol. Genet. Metab. 94:255-8 24097415 Pubmed 2014 Novel association of early onset hepatocellular carcinoma with transaldolase deficiency Leduc, Charles A Crouch, Elizabeth E Wilson, Ashley Lefkowitch, Jay Wamelink, Mirjam M C Jakobs, Cornelis Salomons, Gajja S Sun, Xiaoyun Shen, Yufeng Chung, Wendy K JIMD Rep 12:121-7 Reactome Database ID Release 78 6791462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6791462 Reactome R-HSA-6791462 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6791462.2 TALDO1 deficiency: failed conversion of SH7P, GA3P to Fru(6)P, E4P TALDO1 deficiency: failed conversion of SH7P, GA3P to Fru(6)P, E4P Mutations in transaldolase 1 (TALDO1), an enzyme of the pentose phosphate pathway that normally mediates the reversible interconversion of sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate to form D-fructose 6-phosphate and D-erythrose 4-phosphate, have been associated with congenital liver disease (Wamelink et al. 2008). Authored: D'Eustachio, Peter, 2015-08-18 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-08-18 2.2.1.2 Defective TALDO1 does not transform SH7P, GA3P to Fru(6)P, E4P Defective TALDO1 does not transform SH7P, GA3P to Fru(6)P, E4P Defective TALDO1 (transaldolase 1) fails to transform sedoheptulose 7-phosphate (SH7P) and glyceraldehyde 3-phosphate (GA3P) to fructose 6-phosphate (Fru(6)P) and erythrose 4-phosphate (E4P). This defect has been associated with congenital liver disease and an array of other symptoms. The deficiency was first described by Verhoeven and colleagues (2001). Both the range and severity of these abnormalities are variable from patient to patient (Wamelink et al. 2008a; Eyaid et al. 2013). The three missense mutant alleles annotated here are associated with absence of detectable transaldolase activity in tissues from homozygous affected individuals (LeDuc et al. 2014; Verhoeven et al. 2005; Wamelink et al. 2008b). Authored: D'Eustachio, Peter, 2015-08-18 Reviewed: Jassal, Bijay, 2015-08-18 Edited: D'Eustachio, Peter, 2015-08-18 Reactome DB_ID: 29578 1 D-glyceraldehyde 3-phosphate(2-) [ChEBI:59776] D-glyceraldehyde 3-phosphate(2-) D-glyceraldehyde 3-phosphate (2R)-2-hydroxy-3-oxopropyl phosphate D-glyceraldehyde 3-phosphate dianion ChEBI 59776 Reactome DB_ID: 29882 1 sedoheptulose 7-phosphate [ChEBI:15721] sedoheptulose 7-phosphate ChEBI 15721 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5660002 Reactome Database ID Release 78 5659989 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659989 Reactome R-HSA-5659989 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659989.2 Reactome Database ID Release 78 6791055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6791055 Reactome R-HSA-6791055 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6791055.2 Reactome Database ID Release 78 6791465 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6791465 Reactome R-HSA-6791465 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6791465.2 Intestinal saccharidase deficiencies Intestinal saccharidase deficiencies Defects in in two enzymes required for intestinal digestion of dietary carbohydrate, lactase (LCT, a domain of lactase-phlorizin hydrolase protein) and sucrase-isomaltase (SI), are annotated here. The first affects nursing infants; the second affects individuals after weaning.<p>The disaccharide lactose is a major constituent of human breast milk. To be taken up from the gut in the nursing infant, this sugar must first be hydrolyzed by LCT present on the external face of enterocytes in microvilli of the small intestine. Mutations that disrupt LCT activity are associated with acute illness in newborn children as lactose fermentation by gut bacteria leads to severe diarrhea. The condition is effectively treated by feeding affected infants a lactose-free formula. This congenital disease is distinct from the down-regulation of LCT expression after weaning in many human populations that is associated with a milder form of lactose intolerance in adults (Jarvela et al. 2009).<p>The starch in a post-weaning diet is digested by amylases to di- and oligosaccharides that must be further digested to monosaccharides in order to be taken up from the lumen of the small intestine into endothelial cells of the intestinal brush border. If they are not digested, a process in which enterocyte-associated SI plays a central role, they remain in the gut lumen and are fermented by gut bacteria, leading to osmotic and fermentative diarrhea (Naim et al. 2012; Van Beers et al. 1995). Authored: D'Eustachio, Peter, 2015-02-15 Reviewed: Naim, Hassan Y, Amiri, Mahdi, 2015-02-15 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-02-15 3.2.1.20 Defective SI does not hydrolyze Mal Defective SI does not hydrolyze Mal Mutations that disrupt the catalytic activity or strongly interfere with proper folding, glycosylation and transport of SI (sucrase-isomaltase) block the cleavage of maltose (Mal) to glucose in the gut lumen. Affected individuals can develop severe diarrhea; this symptom is managed by excluding indigestible sugars from the diet (Gray et al. 1976; Ritz et al. 2003; Semenza et al. 1965). A variety of SI mutant alleles have been described. Three missense mutations that are associated with severe loss of SI activity in vivo are annotated here (Alfalah et al. 2009;,Ouwendijk et al. 1996; Sander et al. 2006; Spodsberg et al. 2001). All missense mutant alleles that have been characterized to date encode proteins that fail to reach the lumenal plasma membrane or cannot associate stably with it; one missense mutation not annotated here encodes a polypeptide that undergoes an intracellular cleavage and is secreted as the active enzyme (Jacob et al. 2000). Authored: D'Eustachio, Peter, 2015-02-15 Reviewed: Naim, Hassan Y, Amiri, Mahdi, 2015-02-15 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-02-15 Reactome DB_ID: 109276 1 extracellular region GO 0005576 Reactome DB_ID: 188986 1 maltose [ChEBI:17306] maltose ChEBI 17306 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5659923 SI mutant dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004558 GO molecular function Reactome Database ID Release 78 9631941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631941 Reactome Database ID Release 78 5659922 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659922 Reactome R-HSA-5659922 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659922.3 11340066 Pubmed 2001 Molecular basis of aberrant apical protein transport in an intestinal enzyme disorder Spodsberg, Nikolaj Jacob, Ralf Alfalah, Marwan Zimmer, Klaus-Peter Naim, Hassan Y J. Biol. Chem. 276:23506-10 1256470 Pubmed 1976 Sucrase-isomaltase deficiency. Absence of an inactive enzyme variant Gray, Gary M Conklin, Kenneth A Townley, R R W N. Engl. J. Med. 294:750-3 14724820 Pubmed 2003 Congenital sucrase-isomaltase deficiency because of an accumulation of the mutant enzyme in the endoplasmic reticulum Ritz, Valentina Alfalah, Marwan Zimmer, Klaus-Peter Schmitz, Jacques Jacob, Ralf Naim, Hassan Y Gastroenterology 125:1678-85 16329100 Pubmed 2006 Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption Sander, Petra Alfalah, Marwan Keiser, Markus Korponay-Szabo, Ilma Kovács, Judit B Leeb, Tosso Naim, Hassan Y Hum. Mutat. 27:119 19121318 Pubmed 2009 Compound heterozygous mutations affect protein folding and function in patients with congenital sucrase-isomaltase deficiency Alfalah, Marwan Keiser, Markus Leeb, Tosso Zimmer, Klaus-Peter Naim, Hassan Y Gastroenterology 136:883-92 10903344 Pubmed 2000 Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme Jacob, Ralf Zimmer, Klaus-Peter Schmitz, Jacques Naim, Hassan Y J. Clin. Invest. 106:281-7 5849827 Pubmed 1965 Lack of some intestinal maltases in a human disease transmitted by a single genetic factor Semenza, G Auricchio, S Rubino, A Prader, A Welsh, J D Biochim. Biophys. Acta 105:386-9 8609217 Pubmed 1996 Congenital sucrase-isomaltase deficiency. Identification of a glutamine to proline substitution that leads to a transport block of sucrase-isomaltase in a pre-Golgi compartment Ouwendijk, Joke Moolenaar, Catharina E Peters, Wilma J Hollenberg, Cornelis P Ginsel, Leo A Fransen, Jack A M Naim, Hassan Y J. Clin. Invest. 97:633-41 3.2.1.20 Defective SI does not hydrolyze iMal Defective SI does not hydrolyze iMal Mutations that disrupt the catalytic activity or strongly interfere with proper folding, glycosylation and transport of SI (sucrase-isomaltase) are inferred to block the cleavage of isomaltose (iMal) to glucose, based on the experimentally demonstrated failure of these SI mutant proteins to hydrolyze maltose (e.g., Sander et al. 2006) and the broad substrate specificity of the normal enzyme (Sim et al. 2010). Authored: D'Eustachio, Peter, 2015-02-15 Reviewed: Naim, Hassan Y, Amiri, Mahdi, 2015-02-15 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-02-15 Reactome DB_ID: 109276 1 Reactome DB_ID: 5659875 1 isomaltose [ChEBI:28189] isomaltose ChEBI 28189 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5659923 Reactome Database ID Release 78 9631871 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631871 Reactome Database ID Release 78 5659879 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659879 Reactome R-HSA-5659879 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659879.2 20356844 Pubmed 2010 Structural basis for substrate selectivity in human maltase-glucoamylase and sucrase-isomaltase N-terminal domains Sim, Lyann Willemsma, Carly Mohan, Sankar Naim, Hassan Y Pinto, B Mario Rose, David R J. Biol. Chem. 285:17763-70 3.2.1.48 Defective SI does not hydrolyze Suc Defective SI does not hydrolyze Suc Mutations that disrupt the catalytic activity or strongly interfere with proper folding, glycosylation and transport of SI (sucrase-isomaltase) are inferred to block the cleavage of sucrose (Suc) to glucose and fructose, based on the experimentally demonstrated failure of these SI mutant proteins to hydrolyze maltose (e.g., Sander et al. 2006) and the broad substrate specificity of the normal enzyme (Sim et al. 2010). Authored: D'Eustachio, Peter, 2015-02-15 Reviewed: Naim, Hassan Y, Amiri, Mahdi, 2015-02-15 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-02-15 Reactome DB_ID: 109276 1 Reactome DB_ID: 188980 1 sucrose [ChEBI:17992] sucrose ChEBI 17992 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5659923 GO 0004575 GO molecular function Reactome Database ID Release 78 9631835 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631835 Reactome Database ID Release 78 5659926 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659926 Reactome R-HSA-5659926 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659926.2 3.2.1.20 Defective SI does not hydrolyze maltotriose Defective SI does not hydrolyze maltotriose Mutations that disrupt the catalytic activity or strongly interfere with proper folding, glycosylation and transport of SI (sucrase-isomaltase) are inferred to block the cleavage of maltotriose to maltose and glucose, based on the experimentally demonstrated failure of these SI mutant proteins to hydrolyze maltose (e.g., Sander et al. 2005) and the broad substrate specificity of the normal enzyme (Sim et al. 2010). Authored: D'Eustachio, Peter, 2015-02-15 Reviewed: Naim, Hassan Y, Amiri, Mahdi, 2015-02-15 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-02-15 Reactome DB_ID: 109276 1 Reactome DB_ID: 191103 1 alpha-maltotriose [ChEBI:27931] alpha-maltotriose ChEBI 27931 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5659923 Reactome Database ID Release 78 9631884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631884 Reactome Database ID Release 78 5659899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659899 Reactome R-HSA-5659899 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659899.2 3.2.1.108 Defective LCT does not hydrolyze Lac Defective LCT does not hydrolyze Lac Mutations that disrupt the catalytic activity of LCT (lactase) block the cleavage of lactose (Lac) to galactose and glucose in the gut lumen and cause lactose intolerance in nursing infants. Affected individuals can develop severe diarrhea; the disease can be effectively managed by complete exclusion of lactose from the diet. A variety of LCT mutant alleles have been described. Two missense mutations that are associated with severe loss of lactase activity in vivo are annotated here (Kuokkanen et al. 2006; Torniainen et al. 2009). Authored: D'Eustachio, Peter, 2015-02-15 Reviewed: Naim, Hassan Y, Amiri, Mahdi, 2015-02-15 Reviewed: Jassal, Bijay, 2015-01-29 Edited: D'Eustachio, Peter, 2015-02-15 Reactome DB_ID: 109276 1 Reactome DB_ID: 188973 1 lactose [ChEBI:17716] lactose ChEBI 17716 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5657985 LCT mutant dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0000016 GO molecular function Reactome Database ID Release 78 9631958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631958 Reactome Database ID Release 78 5658001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5658001 Reactome R-HSA-5658001 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5658001.2 19161632 Pubmed 2009 Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD) Torniainen, Suvi Freddara, Roberta Routi, Taina Gijsbers, Carolien Catassi, Carlo Höglund, Pia Savilahti, Erkki Järvelä, Irma BMC Gastroenterol 9:8 16400612 Pubmed 2006 Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency Kuokkanen, Mikko Kokkonen, Jorma Enattah, Nabil Sabri Ylisaukko-Oja, Tero Komu, Hanna Varilo, Teppo Peltonen, Leena Savilahti, Erkki Järvelä, Irma Am. J. Hum. Genet. 78:339-44 Reactome Database ID Release 78 5659898 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5659898 Reactome R-HSA-5659898 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5659898.2 19639477 Pubmed 2009 Molecular genetics of human lactase deficiencies Järvelä, Irma Torniainen, Suvi Kolho, Kaija-Leena Ann. Med. 41:568-75 23103643 Pubmed 2012 Congenital sucrase-isomaltase deficiency: heterogeneity of inheritance, trafficking, and function of an intestinal enzyme complex Naim, Hassan Y Heine, Martin Zimmer, Klaus-Peter J. Pediatr. Gastroenterol. Nutr. 55:S13-20 7555019 Pubmed 1995 Intestinal brush border glycohydrolases: structure, function, and development Van Beers, Eric H Büller, Hans A Grand, Richard J Einerhand, Alexandra W Dekker, Jan Crit. Rev. Biochem. Mol. Biol. 30:197-262 Reactome Database ID Release 78 5663084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5663084 Reactome R-HSA-5663084 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5663084.3 Phenylketonuria Phenylketonuria Phenylalanine hydroxylase (PAH) normally catalyzes the conversion of phenylalanine to tyrosine. In the absence of functional PAH, phenylalanine accumulates to high levels in the blood and is converted to phenylpyruvate and phenyllactate (Clemens et al. 1990; Langenbeck et al. 1992; Mitchell et al. 2011). The extent of these conversions is modulated by genetic factors distinct from PAH, as siblings with the identical PAH defect can produce different amounts of them (Treacy et al. 1996).<p>Both L-amino acid oxidase (Boulland et al. 2004) and Kynurenine--oxoglutarate transaminase 3 (Han et al. 2004) can catalyze the conversion of phenylalanine to phenylpyruvate and lactate dehydrogenase can catalyze the conversion of the latter molecule to phenyllactate (Meister 1950), in reactions not annotated here. Authored: D'Eustachio, P, 2012-03-04 Reviewed: Jassal, B, 2012-03-16 Edited: D'Eustachio, P, 2012-03-16 1.14.16.1 Defective PAH does not hydroxylate L-Phe to L-Tyr Defective PAH does not hydroxylate L-Phe to L-Tyr Inactivating mutations of cytosolic phenylalanine hydroxylase (PAH) block the normal reaction of phenylalanine, molecular oxygen and tetrahydrobiopterin to form tyrosine, water, and 4 alpha-hydroxytetrahydrobiopterin. Excess phenylalanine accumulates as a result, driving the formation of abnormally high levels of phenylpyruvate, and phenyllactate (Guldberg et al. 1996; Mitchell et al. 2011) in reactions not annotated here. Authored: Jassal, Bijay, 2014-12-08 Reviewed: D'Eustachio, Peter, 2015-01-28 Edited: Jassal, Bijay, 2014-12-08 Reactome DB_ID: 29502 1 L-phenylalanine zwitterion [ChEBI:58095] L-phenylalanine zwitterion L-phenylalanine phenylalanine [NH3+][C@@H](Cc1ccccc1)C([O-])=O C9H11NO2 (2S)-2-ammonio-3-phenylpropanoate (2S)-2-azaniumyl-3-phenylpropanoate COLNVLDHVKWLRT-QMMMGPOBSA-N 165.18910 InChI=1S/C9H11NO2/c10-8(9(11)12)6-7-4-2-1-3-5-7/h1-5,8H,6,10H2,(H,11,12)/t8-/m0/s1 ChEBI 58095 Reactome DB_ID: 29870 1 5,6,7,8-tetrahydrobiopterin [ChEBI:15372] 5,6,7,8-tetrahydrobiopterin ChEBI 15372 Reactome DB_ID: 29368 1 dioxygen [ChEBI:15379] dioxygen ChEBI 15379 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9631879 PAH S40L:Fe2+ tetramer [cytosol] PAH S40L:Fe2+ tetramer Reactome DB_ID: 71067 4 iron(2+) [ChEBI:29033] iron(2+) FE (II) ION Fe(2+) Fe(II) Ferrous ion Fe2+ iron ion(2+) ChEBI 29033 Reactome DB_ID: 5649486 4 UniProt:P00439 PAH PAH PAH FUNCTION Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.ACTIVITY REGULATION N-terminal region of PAH is thought to contain allosteric binding sites for phenylalanine and to constitute an 'inhibitory' domain that regulates the activity of a catalytic domain in the C-terminal portion of the molecule.PATHWAY Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 1/6.SUBUNIT Homodimer and homotetramer.PTM Phosphorylation at Ser-16 increases basal activity and facilitates activation by the substrate phenylalanine.POLYMORPHISM The Glu-274 variant occurs on approximately 4% of African-American PAH alleles. The enzyme activity of the variant protein is indistinguishable from that of the wild-type form.SIMILARITY Belongs to the biopterin-dependent aromatic amino acid hydroxylase family. UniProt P00439 L-serine 40 replaced with L-leucine 40 EQUAL L-serine removal [MOD:01646] 2 EQUAL 452 EQUAL Reactome Database ID Release 78 9631879 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631879 Reactome R-HSA-9631879 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9631879.2 GO 0004505 GO molecular function Reactome Database ID Release 78 9631945 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631945 Reactome Database ID Release 78 5649483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5649483 Reactome R-HSA-5649483 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5649483.3 8889590 Pubmed 1996 Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations Guldberg, P Mallmann, R Henriksen, KF Güttler, F Hum Mutat 8:276-9 21555948 Pubmed 2011 Phenylalanine hydroxylase deficiency Mitchell, John J Trakadis, Yannis J Scriver, Charles R Genet. Med. 13:697-707 Reactome Database ID Release 78 2160456 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2160456 Reactome R-HSA-2160456 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2160456.2 2116554 Pubmed 1990 Plasma concentrations of phenyllactic acid in phenylketonuria Clemens, PC Schunemann, MH Hoffmann, GF Kohlschutter, A J Inherit Metab Dis 13:227-8 17356132 Pubmed 2007 Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation Boulland, ML Marquet, J Molinier-Frenkel, V Moller, P Guiter, C Lasoudris, F Copie-Bergman, C Baia, M Gaulard, P Leroy, K Castellano, F Blood 110:220-7 15606768 Pubmed 2004 pH dependence, substrate specificity and inhibition of human kynurenine aminotransferase I Han, Q Li, J Li, J Eur J Biochem 271:4804-14 1583868 Pubmed 1992 A synopsis of the unconjugated acidic transamination metabolites of phenylalanine in phenylketonuria Langenbeck, U Behbehani, A Mench-Hoinowski, A J Inherit Metab Dis 15:136-44 8892014 Pubmed 1996 In vivo disposal of phenylalanine in phenylketonuria: a study of two siblings Treacy, E Pitt, JJ Seller, K Thompson, GN Ramus, S Cotton, RG J Inherit Metab Dis 19:595-602 15421980 Pubmed 1950 Reduction of alpha gamma-diketo and alpha-keto acids catalyzed by muscle preparations and by crystalline lactic dehydrogenase Meister, Alton J Biol Chem 184:117-29 Defects in vitamin and cofactor metabolism Defects in vitamin and cofactor metabolism Vitamins are essential nutrients, required in small amounts from the diet for the normal growth and development of a multicellular organism. Where there is vitamin deficiency, either by poor diet or a defect in metabolic conversion, diseases called Avitaminoses occur. Currently, cobalamin (Cbl, vitamin B12) metabolic defects are described below (Chapter 155 in The Metabolic and Molecular Bases of Inherited Disease, 8th ed, Scriver et al. 2001) Authored: Jassal, B, 2013-04-18 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-18 Defects in cobalamin (B12) metabolism Defects in cobalamin (B12) metabolism Cobalamin (Cbl, vitamin B12) is a nutrient essential for normal functioning of the brain and nervous system and for the formation of blood. Cbl-dependent methionine synthase (MTR) is required for conversion of 5-methyltetrahydrofolate (metTHF) to tetrahydrofolate (THF), in addition to its role in conversion of homocysteine to methionine. In Cbl deficiency, and in inborn errors of Cbl metabolism that affect function of methionine synthase, inability to regenerate THF from metTHF results in decreased function of folate-dependent reactions that are involved in 2 steps of purine biosynthesis and thymidylate synthesis. Cbl deficiency results in hyperhomocysteinemia (due to defects in the conversion of homocysteine to methionine which requires Cbl as a cofactor) and increased levels of methylmalonic acid (MMA). Methionine is used in myelin production, protein, neurotransmitter, fatty acid and phospholipid production and DNA methylation. Symptoms of Cbl deficiency are bone marrow promegaloblastosis (megaloblastic anemia) due to the inhibition of DNA synthesis (specifically purines and thymidine) and neurological symptoms. The defective genes involved in Cbl deficiencies are described below (Froese & Gravel 2010, Nielsen et al. 2012, Whitehead 2006, Watkins & Rosenblatt 2011, Fowler 1998). Authored: Jassal, B, 2013-04-18 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-18 Defective CBLIF causes IFD Defective CBLIF causes IFD Defective CBLIF causes intrinsic factor deficiency Defects in cobalamin binding intrinsic factor CBLIF, aka gastric intrinsic factor GIF) cause hereditary intrinsic factor deficiency (IFD, aka congenital pernicious anemia; MIM:261000). IFD is an autosomal recessive disorder characterized by megaloblastic anemia (Tanner et al. 2005). Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective CBLIF does not bind Cbl Defective CBLIF does not bind Cbl Gastric parietal cells secrete cobalamin binding intrinsic factor (CBLIF aka gastric intrinsic factor GIF) which binds tightly to free cobalamin (Cbl). Cbl must bind to CBLIF to be absorbed from the small intestine. Defects in CBLIF cause hereditary intrinsic factor deficiency (IFD, aka congenital pernicious anemia; MIM:261000). IFD is an autosomal recessive disorder characterized by megaloblastic anemia. The splice site mutation c.79+1G>A (p.S27Cfs*23) is apparently a Western Caucasian founder mutation (Tanner et al. 2005, Tanner et al. 2012). Authored: Jassal, B, 2013-04-25 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-25 Reactome DB_ID: 3315461 1 UniProt:P27352 CBLIF CBLIF CBLIF GIF IFMH FUNCTION Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After interaction with CUBN, the CBLIF-cobalamin complex is internalized via receptor-mediated endocytosis.SUBUNIT Interacts with CUBN (via CUB domains).TISSUE SPECIFICITY Gastric mucosa.SIMILARITY Belongs to the eukaryotic cobalamin transport proteins family. UniProt P27352 Replacement of residues 27 to 48 by CEYDVFPRRSGKQLPWGRGCDL 19 EQUAL 417 EQUAL Reactome DB_ID: 3000125 1 cob(III)alamin [ChEBI:28911] cob(III)alamin cobalamin(1+) Cobalamin (III) cobalamin(III) alpha-(5,6-dimethylbenzimidazolyl)cobamide Cbl ChEBI 28911 Reactome Database ID Release 78 3315455 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3315455 Reactome R-HSA-3315455 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3315455.2 15738392 Pubmed 2005 Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene Tanner, Stephan M Li, Zhongyuan Perko, James D Oner, Cihan Cetin, Mualla Altay, Cigdem Yurtsever, Zekiye David, Karen L Faivre, Laurence Ismail, Essam A Gräsbeck, Ralph de la Chapelle, A Proc. Natl. Acad. Sci. U.S.A. 102:4130-3 22929189 Pubmed 2012 Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns Tanner, Stephan M Sturm, Amy C Baack, Elizabeth C Liyanarachchi, Sandya de la Chapelle, A Orphanet J Rare Dis 7:56 Reactome Database ID Release 78 3359457 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359457 Reactome R-HSA-3359457 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359457.2 Defective AMN causes MGA1 Defective AMN causes MGA1 Defective AMN causes hereditary megaloblastic anemia 1 Defects in AMN cause recessive hereditary megaloblastic anemia 1 (RH-MGA1 aka MGA1 Norwegian type or Imerslund-Grasbeck syndrome, I-GS; MIM:261100). The Norwegian cases described by Imerslund were due to defects in AMN (Imerslund 1960). The resultant malabsorption of Cbl (vitamin B12) leads to impaired B12-dependent folate metabolism and ultimately impaired thymine synthesis and DNA replication. Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective AMN does not transport GIF:Cbl Defective AMN does not transport GIF:Cbl In preparation for internalisation, the gastric intrinsic factor:cobalamin (GIF:Cbl) complex interacts with the cubilin:protein amnionless complex (CUBN:AMN, Cubam). CUBN is a multisubstrate cell surface receptor facilitating uptake of lipoproteins, vitamins and iron. Protein amnionless (AMN) is a necessary component which directs subcellular localization and endocytosis of GIF:Cbl. Defects in AMN cause recessive hereditary megaloblastic anemia 1 (RH-MGA1 aka MGA1 Norwegian type or Imerslund-Grasbeck syndrome, I-GS; MIM:261100). The Finnish cases described by Grasbeck et al. were caused by defects in CUBN whereas the Norwegian cases described by Imerslund were due to defects in AMN (Grasbeck et al. 1960, Imerslund 1960 respectively). The resultant malabsorption of Cbl (vitamin B12) leads to impaired B12-dependent folate metabolism and ultimately impaired thymine synthesis and DNA replication. Cells involved in erythropoiesis are particularly affected. Two common mutations in AMN are T34I and G5Afs*12 (Tanner et al. 2003). Authored: Jassal, B, 2013-04-18 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-18 Reactome DB_ID: 5654975 1 CUBN:AMN mutants [plasma membrane] CUBN:AMN mutants Converted from EntitySet in Reactome Reactome DB_ID: 3299662 1 AMN mutants [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AMN T41I [plasma membrane] AMN G5Afs*12 [plasma membrane] UniProt Q9BXJ7 Reactome DB_ID: 264843 1 UniProt:O60494 CUBN CUBN CUBN IFCR FUNCTION Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake (PubMed:9572993, PubMed:10371504, PubMed:11717447, PubMed:11606717, PubMed:14576052). Acts together with LRP2 to mediate endocytosis of high-density lipoproteins, GC, hemoglobin, ALB, TF and SCGB1A1. Acts together with AMN to mediate endocytosis of the CBLIF-cobalamin complex (PubMed:9572993, PubMed:14576052). Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the CBLIF-cobalamin complex. Ligand binding requires calcium (PubMed:9572993). Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface.SUBUNIT Interacts with AMN (PubMed:14576052, PubMed:29402915, PubMed:20237569, PubMed:30523278). Component of the cubam complex composed of one CUBN trimer and one AMN chain (PubMed:30523278). The cubam complex can dimerize (By similarity). Interacts with LRP2 in a dual-receptor complex in a calcium-dependent manner. Found in a complex with PID1/PCLI1, LRP1 and CUBNI. Interacts with LRP1 and PID1/PCLI1.TISSUE SPECIFICITY Detected in kidney cortex (at protein level) (PubMed:9572993). Expressed in kidney proximal tubule cells, placenta, visceral yolk-sac cells and in absorptive intestinal cells. Expressed in the epithelium of intestine and kidney.DOMAIN The CUB domains 5 to 8 mediate binding to CBLIF and ALB. CUB domains 1 and 2 mediate interaction with LRP2.DOMAIN The cubam complex is composed of a 400 Angstrom long stem and a globular crown region. The stem region is probably formed by AMN and the CUBN N-terminal region, including the EGF-like domains. The crown is probably formed by the CUBN CUB domains.PTM The precursor is cleaved by a trans-Golgi proteinase furin, removing a propeptide.PTM N-glycosylated. UniProt O60494 36 EQUAL 3623 EQUAL Reactome Database ID Release 78 5654975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5654975 Reactome R-HSA-5654975 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5654975.1 Reactome DB_ID: 3000147 1 CBLIF:Cbl [extracellular region] CBLIF:Cbl Reactome DB_ID: 2980918 1 19 EQUAL 417 EQUAL Reactome DB_ID: 3000125 1 Reactome Database ID Release 78 3000147 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000147 Reactome R-HSA-3000147 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000147.2 Reactome Database ID Release 78 3296477 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3296477 Reactome R-HSA-3296477 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3296477.1 13828999 Pubmed 1960 Selective vitamin B12 malabsorption and proteinuria in young people. A syndrome GRASBECK, R GORDIN, R KANTERO, I KUHLBACK, B Acta Med Scand 167:289-96 13852753 Pubmed 1960 Idiopathic chronic megaloblastic anemia in children IMERSLUND, O Acta Paediatr Suppl 49:1-115 12590260 Pubmed 2003 Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia Tanner, Stephan M Aminoff, M Wright, Fred A Liyanarachchi, Sandya Kuronen, Mervi Saarinen, Anne Massika, Orit Mandel, H Broch, Harald de la Chapelle, A Nat. Genet. 33:426-9 Reactome Database ID Release 78 3359462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359462 Reactome R-HSA-3359462 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359462.2 Defective CUBN causes MGA1 Defective CUBN causes MGA1 Defective CUBN causes hereditary megaloblastic anemia 1 Defects in the CUBN gene cause recessive hereditary megaloblastic anemia 1 (RH-MGA1 aka MGA1 Finnish type or Imerslund-Grasbeck syndrome, I-GS; MIM:261100). The Finnish cases described by Grasbeck et al. were caused by defects in CUBN (Grasbeck et al. 1960). The resultant malabsorption of Cbl (cobalamin, vitamin B12) leads to impaired B12-dependent folate metabolism and ultimately impaired thymine synthesis and DNA replication. Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective CUBN does not transport GIF:Cbl Defective CUBN does not transport GIF:Cbl In preparation for internalisation, the gastric intrinsic factor:cobalamin (GIF:Cbl) complex interacts with the cubilin:protein amnionless complex (CUBN:AMN). CUBN is a cotransporter facilitating uptake of lipoproteins, vitamins and iron. Protein amnionless (AMN) is a necessary component which directs subcellular localization and endocytosis of GIF:Cbl.<br><br>Defects in CUBN cause recessive hereditary megaloblastic anemia 1 (RH-MGA1 aka MGA1 Finnish type or Imerslund-Grasbeck syndrome, I-GS; MIM:261100). The Finnish cases described by Grasbeck et al. were caused by defects in CUBN whereas the Norwegian cases described by Imerslund were due to defects in AMN (Grasbeck et al. 1960, Imerslund 1960 respectively). The resultant malabsorption of Cbl (vitamin B12) leads to impaired B12-dependent folate metabolism and ultimately impaired thymine synthesis and DNA replication. Cells involved in erythropoiesis are particularly affected. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries, in Norway and highest in Finland (0.8 in 100,000). The P1297L mutation in CUBN is most commonly found in Finland (Aminoff et al. 1999, Kristiansen et al. 2000). Authored: Jassal, B, 2013-04-18 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-18 Reactome DB_ID: 5654976 1 CUBN P1297L:AMN [plasma membrane] CUBN P1297L:AMN Reactome DB_ID: 264825 1 UniProt:Q9BXJ7 AMN AMN AMN UNQ513/PRO1028 FUNCTION Membrane-bound component of the endocytic receptor formed by AMN and CUBN (PubMed:14576052, PubMed:30523278, PubMed:29402915). Required for normal CUBN glycosylation and trafficking to the cell surface (PubMed:14576052, PubMed:29402915). The complex formed by AMN and CUBN is required for efficient absorption of vitamin B12 (PubMed:12590260, PubMed:14576052, PubMed:26040326). Required for normal CUBN-mediated protein transport in the kidney (Probable).SUBUNIT Interacts (via extracellular region) with CUBN/cubilin, giving rise to a huge complex containing one AMN chain and three CUBN chains.TISSUE SPECIFICITY Detected in proximal tubules in the kidney cortex (at protein level) (PubMed:14576052, PubMed:29402915). Long isoforms are highly expressed in small intestine, colon and kidney (renal proximal tubule epithelial cells). Shorter isoforms are detected at lower levels in testis, thymus and peripheral blood leukocytes.DOMAIN The complex formed by AMN and CUBN is composed of a 400 Angstrom long stem and a globular crown region. The stem region is probably formed by AMN and the CUBN N-terminal region, including the EGF-like domains. The crown is probably formed by the CUBN CUB domains.PTM N-glycosylated.PTM A soluble form arises by proteolytic removal of the membrane anchor.MISCELLANEOUS The role of Amn in embryonic development seems to be species specific. In mice, null mutations lead to embryonic lethality. Human mutations give rise to much milder symptoms. 20 EQUAL 453 EQUAL Reactome DB_ID: 3296479 1 L-proline 1297 replaced with L-leucine 1297 EQUAL L-proline removal [MOD:01645] 36 EQUAL 3623 EQUAL Reactome Database ID Release 78 5654976 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5654976 Reactome R-HSA-5654976 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5654976.1 Reactome DB_ID: 3000147 1 Reactome Database ID Release 78 3296462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3296462 Reactome R-HSA-3296462 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3296462.1 10080186 Pubmed 1999 Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1 Aminoff, M Carter, J E Chadwick, R B Johnson, C Gräsbeck, R Abdelaal, M A Broch, H Jenner, L B Verroust, P J Moestrup, S K de la Chapelle, A Krahe, R Nat. Genet. 21:309-13 10887099 Pubmed 2000 Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin Kristiansen, M Aminoff, M Jacobsen, C de la Chapelle, A Krahe, R Verroust, P J Moestrup, S K Blood 96:405-9 Reactome Database ID Release 78 3359463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359463 Reactome R-HSA-3359463 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359463.2 Defective ABCD4 causes MAHCJ Defective ABCD4 causes MAHCJ Defective ABCD4 causes methylmalonic aciduria and homocystinuria, cblj type (MAHCJ) ATP-binding cassette sub-family D member 4 (ABCD4) is thought to mediate the lysosomal export of cobalamin (Cbl aka vitamin B12) into the cytosol, making it available for the production of Cbl cofactors. Cbl is an important cofactor for correct haematological and neurological functions. Defects in ABCD4 can cause methylmalonic aciduria and homocystinuria, cblJ type (MAHCJ; MIM:614857), a genetically heterogeneous metabolic disorder of Cbl metabolism characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinically, symptoms include feeding difficulties, poor growth, hypotonia, lethargy, anaemia and delayed development (Coelho et al. 2012). Authored: Jassal, Bijay, 2015-03-13 Reviewed: Shukla, Suneet, 2015-09-15 Edited: Jassal, Bijay, 2015-03-13 7.6.2.8 Defective ABCD4:LMBRD1 does not transport Cbl from lysosomal lumen to cytosol Defective ABCD4:LMBRD1 does not transport Cbl from lysosomal lumen to cytosol ATP-binding cassette sub-family D member 4 (ABCD4) is thought to mediate the lysosomal export of cobalamin (Cbl aka vitamin B12) into the cytosol, making it available for the production of Cbl cofactors. Cbl is an important cofactor for correct haematological and neurological functions. Defects in ABCD4 can cause methylmalonic aciduria and homocystinuria, cblJ type (MAHCJ; MIM:614857), a genetically heterogeneous metabolic disorder of Cbl metabolism characterised by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinically, symptoms include feeding difficulties, poor growth, hypotonia, lethargy, anaemia and delayed development. Mutations causing MAHCJ include Y319C and E583Lfs*9 (Coelho et al. 2012). Authored: Jassal, Bijay, 2015-03-13 Reviewed: Shukla, Suneet, 2015-09-15 Edited: Jassal, Bijay, 2015-03-13 Reactome DB_ID: 29356 1 Reactome DB_ID: 3000239 1 Reactome DB_ID: 113592 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5683323 ABCD4 mutant:LBRD1 complexes [lysosomal membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0015420 GO molecular function Reactome Database ID Release 78 9631842 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631842 Reactome Database ID Release 78 5683325 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683325 Reactome R-HSA-5683325 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683325.3 22922874 Pubmed 2012 Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism Coelho, David Kim, Jaeseung C Miousse, Isabelle R Fung, Stephen du Moulin, Marcel Buers, Insa Suormala, T Burda, Patricie Frapolli, Michele Stucki, Martin Nürnberg, P Thiele, Holger Robenek, Horst Höhne, Wolfgang Longo, Nicola Pasquali, Marzia Mengel, Eugen Watkins, D Shoubridge, EA Majewski, Jacek Rosenblatt, DS Fowler, Brian Rutsch, F Baumgartner, MR Nat. Genet. 44:1152-5 Reactome Database ID Release 78 5683329 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683329 Reactome R-HSA-5683329 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683329.2 Defective MMACHC causes MAHCC Defective MMACHC causes MAHCC Defective MMACHC causes methylmalonic aciduria and homocystinuria type cblC Defects in MMACHC cause methylmalonic aciduria and homocystinuria type cblC (MMAHCC; MIM:277400). MMAHCC is the most common disorder of cobalamin metabolism and is characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have developmental, haematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings (Lerner-Ellis et al. 2006). Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective MMACHC does not decyanate CNCbl Defective MMACHC does not decyanate CNCbl Methylmalonic aciduria and homocystinuria type C protein (MMACHC aka cblC protein) is suggested to be involved in the binding and intracellular transport of cobalamin (Cbl aka vitamin B12, cob(III)alamin). MMACHC can catalyse the removal of the "R" group (formally known as the upper axial ligand) from R-Cbl (where R can be Ado-, Me- or CN-) resulting in the reduction of Cbl (+3 oxidation state) to cob(II)alamin (B12r, vitamin B12r, +2 oxidation state) (Hannibal et al. 2009). Cob(II)alamin is escorted by MMACHC to its destination enzyme partners in the mitochondria and cytosol.<br><br>Defects in MMACHC cause methylmalonic aciduria and homocystinuria type cblC (MMAHCC; MIM:277400). MMAHCC is the most common disorder of cobalamin metabolism and is characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have developmental, haematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings (Lerner-Ellis et al. 2006). This disease is usually seen in infancy or childhood but can also present in later life. The common mutations 271dupA (p.R91Kfs*14) and R111*, found in approximately 40% and 5% of patients respectively, and W203* (this mutation is extremely common in Chinese patients where the c.271dupA mutation is virtually unknown) present in early-onset forms of the disease (Morel et al. 2006, Lerner-Ellis et al. 2006, Lerner-Ellis et al. 2009, Liu et al. 2010) whereas the mutations R132* and R161Q present in adulthood (Lerner-Ellis et al. 2009, Liu et al. 2010). Authored: Jassal, B, 2013-04-29 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-29 Reactome DB_ID: 70106 1 Converted from EntitySet in Reactome Reactome DB_ID: 3318601 1 MMACHC mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMACHC R111* [cytosol] MMACHC R91Kfs*14 [cytosol] MMACHC R132* [cytosol] MMACHC R161Q [cytosol] MMACHC W203* [cytosol] UniProt Q9Y4U1 Reactome DB_ID: 29364 1 Reactome DB_ID: 3149505 1 cyanocob(III)alamin [ChEBI:17439] cyanocob(III)alamin ChEBI 17439 Reactome Database ID Release 78 3318590 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3318590 Reactome R-HSA-3318590 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3318590.3 16714133 Pubmed 2006 Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations Morel, Chantal F Lerner-Ellis, Jordan P Rosenblatt, DS Mol. Genet. Metab. 88:315-21 19447654 Pubmed 2009 Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product Hannibal, Luciana Kim, Jihoe Brasch, Nicola E Wang, Sihe Rosenblatt, DS Banerjee, Ruma Jacobsen, Donald W Mol. Genet. Metab. 97:260-6 20631720 Pubmed 2010 Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria Liu, Mei-Ying Yang, Yan-Ling Chang, Ying-Chen Chiang, Szu-Hui Lin, Shuan-Pei Han, Lian-Shu Qi, Yu Hsiao, Kwang-Jen Liu, Tze-Tze J. Hum. Genet. 55:621-6 16311595 Pubmed 2006 Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type Lerner-Ellis, Jordan P Tirone, Jamie C Pawelek, Peter D Doré, Carole Atkinson, Janet L Watkins, D Morel, Chantal F Fujiwara, T Mary Moras, Emily Hosack, Angela R Dunbar, Gail V Antonicka, Hana Forgetta, Vince Dobson, C Melissa Leclerc, Daniel Gravel, RA Shoubridge, EA Coulton, James W Lepage, Pierre Rommens, JM Morgan, Kenneth Rosenblatt, DS Nat. Genet. 38:93-100 19370762 Pubmed 2009 Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations Lerner-Ellis, Jordan P Anastasio, Natascia Liu, Junhui Coelho, David Suormala, T Stucki, Martin Loewy, Amanda D Gurd, Scott Grundberg, Elin Morel, Chantal F Watkins, D Baumgartner, MR Pastinen, Tomi Rosenblatt, DS Fowler, Brian Hum. Mutat. 30:1072-81 Defective MMACHC does not reduce Cbl Defective MMACHC does not reduce Cbl Methylmalonic aciduria and homocystinuria type C protein (MMACHC aka cblC protein) is suggested to be involved in the binding and intracellular transport of cobalamin (Cbl aka vitamin B12, cob(III)alamin). MMACHC can catalyse the removal of the "R" group (formally known as the upper axial ligand) from R-Cbl (where R can be Ado-, Me- or CN-) resulting in the reduction of Cbl (+3 oxidation state) to cob(II)alamin (B12r, vitamin B12r, +2 oxidation state) (Hannibal et al. 2009). Cob(II)alamin is escorted by MMACHC to its destination enzyme partners in the mitochondria and cytosol.<br><br>Defects in MMACHC cause methylmalonic aciduria and homocystinuria type cblC (MMAHCC; MIM:277400). MMAHCC is the most common disorder of cobalamin metabolism and is characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have developmental, haematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings (Lerner-Ellis et al. 2006). This disease is usually seen in infancy or childhood but can also present in later life. The common mutations 271dupA (p.R91Kfs*14) and R111*, found in approximately 40% and 5% of patients respectively, and W203* (this mutation is extremely common in Chinese patients where the c.271dupA mutation is virtually unknown) present in early-onset forms of the disease (Morel et al. 2006, Lerner-Ellis et al. 2006, Lerner-Ellis et al. 2009, Liu et al. 2010) whereas the mutations R132* and R161Q present in adulthood (Lerner-Ellis et al. 2009, Liu et al. 2010). Authored: Jassal, B, 2013-04-29 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-29 Reactome DB_ID: 70106 1 Converted from EntitySet in Reactome Reactome DB_ID: 3318601 1 Reactome DB_ID: 3000241 1 Reactome DB_ID: 29364 1 Reactome Database ID Release 78 3318576 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3318576 Reactome R-HSA-3318576 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3318576.2 Reactome Database ID Release 78 3359474 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359474 Reactome R-HSA-3359474 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359474.2 Defective MMADHC causes MMAHCD Defective MMADHC causes MMAHCD Defective MMADHC causes methylmalonic aciduria and homocystinuria type cblD Defects in MMADHC cause methylmalonic aciduria and homocystinuria type cblD (MMAHCD; MIM:277410), a disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Coelho et al. 2008). Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective MMADHC does not bind MMACHC:B12r Defective MMADHC does not bind MMACHC:B12r MMACHC:B12r (cob(II)alamin, vitamin B12r) binding to methylmalonic aciduria and homocystinuria type D protein (MMADHC) represents a branch point in the targeted delivery of B12r to either cytosolic or mitochondrial enzymes requiring this cofactor (Mah et al. 2013, Plesa et al. 2011, Deme et al. 2012). Both MMACHC and MMADHC are implicated in the intracellular transport of cobalamins but exact details of the mechanisms involved remain unclear. <br><br>Defects in MMADHC cause methylmalonic aciduria and homocystinuria type cblD (MMAHCD; MIM:277410), a disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Coelho et al. 2008). There are 3 biochemical phenotypes for this disorder; sufferers with homocystinuria (mutants L259P, T182N and Y249C), methylmalonic aciduria (mutants S20*, and R54*), and combined homocystinuria and methylmalonic aciduria (mutants R250* and Y140*) (Coelho et al. 2008, Suormala et al. 2004). Authored: Jassal, B, 2013-04-29 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-29 Reactome DB_ID: 3095903 1 MMACHC:cob(II)alamin [cytosol] MMACHC:cob(II)alamin Reactome DB_ID: 2980949 1 UniProt:Q9Y4U1 MMACHC MMACHC MMACHC FUNCTION Cobalamin (vitamin B12) cytosolic chaperone that catalyzes the reductive decyanation of cyanocob(III)alamin (cyanocobalamin, CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as cofactors and NADPH as cosubstrate (PubMed:18779575, PubMed:19700356, PubMed:21697092, PubMed:25809485). Cyanocobalamin constitutes the inactive form of vitamin B12 introduced from the diet, and is converted into the active cofactors methylcobalamin (MeCbl) involved in methionine biosynthesis, and 5'-deoxyadenosylcobalamin (AdoCbl) involved in the TCA cycle (PubMed:19801555). Forms a complex with the lysosomal transporter ABCD4 and its chaperone LMBRD1, to transport cobalamin across the lysosomal membrane into the cytosol (PubMed:25535791). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR (methionine synthase) which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:21071249, PubMed:27771510). Also acts as a glutathione transferase by catalyzing the dealkylation of the alkylcob(III)alamins MeCbl and AdoCbl, using the thiolate of glutathione for nucleophilic displacement to generate cob(I)alamin and the corresponding glutathione thioether (PubMed:19801555, PubMed:21697092, PubMed:22642810, PubMed:25809485). The conversion of incoming MeCbl or AdoCbl into a common intermediate cob(I)alamin is necessary to meet the cellular needs for both cofactors (PubMed:19801555). Cysteine and homocysteine cannot substitute for glutathione in this reaction (PubMed:19801555).PATHWAY Cofactor biosynthesis; adenosylcobalamin biosynthesis.SUBUNIT Monomer in the absence of bound substrate (PubMed:21697092, PubMed:22642810). Homodimer; dimerization is triggered by binding to FMN or adenosylcobalamin (PubMed:22642810). Interacts with LMBRD1 and ABCD4; the interaction ensures the transport of cobalamin from the lysosome to the cytoplasm (PubMed:25535791). Forms a multiprotein complex with MMADHC, MTR and MTRR; the interaction with MTR could modulate MMACHC-dependent processing of cobalamin (PubMed:27771510). Heterodimer with MMADHC; the interaction might play a role in the regulation of the balance between AdoCbl and MeCbl synthesis (PubMed:21071249, PubMed:23415655, PubMed:26483544).TISSUE SPECIFICITY Widely expressed. Expressed at higher level in fetal liver. Also expressed in spleen, lymph node, thymus and bone marrow. Weakly or not expressed in peripheral blood leukocytes.SIMILARITY Belongs to the MMACHC family. 1 EQUAL 282 EQUAL Reactome DB_ID: 3149479 1 cob(II)alamin [ChEBI:16304] cob(II)alamin ChEBI 16304 Reactome Database ID Release 78 3095903 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3095903 Reactome R-HSA-3095903 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3095903.1 Converted from EntitySet in Reactome Reactome DB_ID: 3318583 1 MMADHC mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMADHC R54* [cytosol] MMADHC S20* [cytosol] MMADHC Y140* [cytosol] MMADHC R250* [cytosol] MMADHC T182N [cytosol] MMADHC Y249C [cytosol] MMADHC L259P [cytosol] UniProt Q9H3L0 Reactome Database ID Release 78 3318571 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3318571 Reactome R-HSA-3318571 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3318571.1 21071249 Pubmed 2011 Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B?? metabolism Plesa, Maria Kim, Jaeseung Paquette, Stéphane G Gagnon, Hubert Ng-Thow-Hing, Christopher Gibbs, Bernard F Hancock, Mark A Rosenblatt, DS Coulton, James W Mol. Genet. Metab. 102:139-48 18385497 Pubmed 2008 Gene identification for the cblD defect of vitamin B12 metabolism Coelho, David Suormala, T Stucki, Martin Lerner-Ellis, Jordan P Rosenblatt, DS Newbold, Robert F Baumgartner, MR Fowler, Brian N. Engl. J. Med. 358:1454-64 23270877 Pubmed 2013 Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism Mah, Wayne Deme, Justin C Watkins, D Fung, Stephen Janer, Alexandre Shoubridge, EA Rosenblatt, DS Coulton, James W Mol. Genet. Metab. 108:112-8 22832074 Pubmed 2012 Structural features of recombinant MMADHC isoforms and their interactions with MMACHC, proteins of mammalian vitamin B12 metabolism Deme, Justin C Miousse, Isabelle R Plesa, Maria Kim, Jaeseung C Hancock, Mark A Mah, Wayne Rosenblatt, DS Coulton, James W Mol. Genet. Metab. 107:352-62 15292234 Pubmed 2004 The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis Suormala, T Baumgartner, MR Coelho, David Zavadakova, Petra Kozich, Viktor Koch, Hans Georg Berghaüser, Martin Wraith, James E Burlina, Alberto Sewell, Adrian Herwig, Jürgen Fowler, Brian J. Biol. Chem. 279:42742-9 Reactome Database ID Release 78 3359473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359473 Reactome R-HSA-3359473 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359473.2 Defective MTRR causes HMAE Defective MTRR causes HMAE Defective MTRR causes methylmalonic aciduria and homocystinuria type cblE Defects in MTRR cause methylcobalamin deficiency type E (cblE; methionine synthase reductase deficiency; MIM:236270) (Wilson et al. 1999). Patients with cblE exhibit megaloblastic anemia and hyperhomocysteinemia. SAM is used as a methyl donor in many biological reactions and demethylation of SAM produces S-adenosylhomocysteine, which is deadenosylated to form homocysteine. Homocysteine remethylation is carried out by MTR, which requires MTRR to maintain enzyme-bound cobalamin (Cbl) in its active form; but in cblE patients, MTR becomes inactivated and thus homocysteine accumulates. Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective MTRR does not convert cob(II)alamin to MeCbl Defective MTRR does not convert cob(II)alamin to MeCbl Methionine synthase reductase (MTRR) is involved in reducing cob(II)alamin (B<sub>12r</sub>) to methylcobalamin (MeCbl), the cofactor form used by methionine synthase (MTR). Regeneration of functional MTR requires reductive methylation via a reaction catalysed by MTRR in which S-adenosylmethionine (AdoMet, SAM) is used as a methyl donor. MTRR requires 1 FMN and 1 FAD per subunit for activity (Wolthers et al. 2007). MTRR exists in a stable complex with MTR, bound through their FMN-binding and C-terminal activation domains respectively (Wolthers & Scrutton 2007, Wolthers & Scrutton 2009).<br><br>When methionine synthase (MTR) is functioning properly, cobalamin (Cbl) is continuously shuttled between two forms, cob(I)alamin and MeCbl. There are 2 half reactions: transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to enzyme-bound cob(I)alamin to form MeCbl; and transfer of the methyl group from MeCbl to homocysteine (HYCS) to form AdoMet, methionine and regenerate cob(I)alamin. From time to time (every few hundred cycles), the enzyme-bound cobalamin is spontaneously oxidized to form cob(II)alamin. When this happens, MTRR in conjunction with MTR catalyzes the reductive methylation of cob(II)alamin to form MeCbl. If MTRR is defective, cob(II)alamin accumulates and methionine synthase is inactivated.<br><br>Defects in MTRR cause methylcobalamin deficiency type E (cblE; MIM:236270) (Wilson et al. 1999). Patients with cblE exhibit megaloblastic anemia and hyperhomocysteinemia. AdoMet is used as a methyl donor in many biological reactions and its demethylation produces homocysteine. Remethylation is carried out by MTR in conjunction with MTRR but in cblE patients, MTR-bound cobalamin cannot be reduced by defective MTRR to form a functional enzyme thus homocysteine accumulates. Mutations in MTRR that cause cblE include Leu576del (Leclerc et al. 1998) and S454L (Zavadakova et al. 2005). In terms of frequency, the most common MTRR mutation is a c.903+469C>T mutation which creates a novel splice site deep in an intron and results in inclusion of a 140-bp insertion in MTRR mRNA (Homolova et al. 2010). Wilson et al. showed that a 66A G polymorphism, resulting in an Ile22Met (I22M) substitution, is associated with susceptibility to folate sensitive neural tube defects (FS NTD; MIM:601634) (Wilson et al. 1999b, Doolin et al. 2002). Serum deficiency of vitamin B<sub>12</sub> increased the effect. Authored: Jassal, B, 2013-04-29 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-04-29 Reactome DB_ID: 9013254 1 mutant MTRR:MTR(cob(II)alamin) [cytosol] mutant MTRR:MTR(cob(II)alamin) Reactome DB_ID: 3149527 1 MTR:Zn2+:cob(II)alamin [cytosol] MTR:Zn2+:cob(II)alamin Reactome DB_ID: 29426 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome DB_ID: 174376 1 UniProt:Q99707 MTR MTR MTR FUNCTION Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol (PubMed:27771510). MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis. Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate (PubMed:27771510). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:27771510).PATHWAY Amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine (MetH route): step 1/1.SUBUNIT Monomer (PubMed:17288554). Dimer (PubMed:17288554). Forms a multiprotein complex with MMACHC, MMADHC AND MTRR (PubMed:17288554, PubMed:27771510).TISSUE SPECIFICITY Widely expressed. Expressed at the highest levels in pancreas, heart, brain, skeletal muscle and placenta. Expressed at lower levels in lung, liver and kidney.DOMAIN Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin (By similarity).MISCELLANEOUS L-homocysteine is bound via the zinc atom.SIMILARITY Belongs to the vitamin-B12 dependent methionine synthase family. UniProt Q99707 1 EQUAL 1265 EQUAL Reactome DB_ID: 3149479 1 Reactome Database ID Release 78 3149527 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3149527 Reactome R-HSA-3149527 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3149527.1 Reactome DB_ID: 9013252 1 mutant MTRR:FMN:FAD [cytosol] mutant MTRR:FMN:FAD Reactome DB_ID: 29386 1 FAD [ChEBI:16238] FAD Flavin adenine dinucleotide ChEBI 16238 Converted from EntitySet in Reactome Reactome DB_ID: 3321956 1 MTRR mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MTRR L576del [cytosol] MTRR I22M [cytosol] MTRR S454L [cytosol] UniProt Q9UBK8 Reactome DB_ID: 73524 1 FMN [ChEBI:17621] FMN Flavin mononucleotide Riboflavin-5-phosphate ChEBI 17621 Reactome Database ID Release 78 9013252 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013252 Reactome R-HSA-9013252 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013252.1 Reactome Database ID Release 78 9013254 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013254 Reactome R-HSA-9013254 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013254.1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 71284 1 S-adenosyl-L-methionine [ChEBI:15414] S-adenosyl-L-methionine ChEBI 15414 Reactome Database ID Release 78 3318563 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3318563 Reactome R-HSA-3318563 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3318563.2 12555939 Pubmed 2002 CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families Zavadakova, P Fowler, B Zeman, J Suormala, T Pristoupilová, K Kozich, V Zavad'áková, P J. Inherit. Metab. Dis. 25:461-76 15714522 Pubmed 2005 cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression Zavadakova, Petra Fowler, Brian Suormala, T Novotna, Zorka Mueller, Peter Hennermann, Julia B Zeman, Jirí Vilaseca, M Antonia Vilarinho, Laura Gutsche, Sven Wilichowski, Ekkehard Horneff, Gerd Kozich, Viktor Hum. Mutat. 25:239-47 20120036 Pubmed 2010 The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria Homolova, Katerina Zavadakova, Petra Doktor, Thomas Koed Schroeder, LD Kozich, Viktor Andresen, Brage S Hum. Mutat. 31:437-44 9501215 Pubmed 1998 Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria Leclerc, D Wilson, A Dumas, R Gafuik, C Song, D Watkins, D Heng, H H Rommens, J M Scherer, Stephen W Rosenblatt, David Gravel, R A Proc. Natl. Acad. Sci. U.S.A. 95:3059-64 10444342 Pubmed 1999 A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida Wilson, A Platt, R Wu, Q Leclerc, D Christensen, B Yang, H Gravel, R A Rozen, R Mol. Genet. Metab. 67:317-23 12375236 Pubmed 2002 Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida Doolin, Marie-Therese Barbaux, Sandrine McDonnell, Maeve Hoess, Katy Whitehead, Alexander S Mitchell, Laura E Am. J. Hum. Genet. 71:1222-6 17892308 Pubmed 2007 Mechanism of coenzyme binding to human methionine synthase reductase revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry Wolthers, Kirsten R Lou, Xiaodong Toogood, Helen S Leys, David Scrutton, Nigel S Biochemistry 46:11833-44 17477549 Pubmed 2007 Protein interactions in the human methionine synthase-methionine synthase reductase complex and implications for the mechanism of enzyme reactivation Wolthers, Kirsten R Scrutton, Nigel S Biochemistry 46:6696-709 19243433 Pubmed 2009 Cobalamin uptake and reactivation occurs through specific protein interactions in the methionine synthase-methionine synthase reductase complex Wolthers, Kirsten R Scrutton, Nigel S FEBS J. 276:1942-51 10484769 Pubmed 1999 Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism Wilson, A Leclerc, D Rosenblatt, David Gravel, R A Hum. Mol. Genet. 8:2009-16 Reactome Database ID Release 78 3359467 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359467 Reactome R-HSA-3359467 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359467.2 Defective MTR causes HMAG Defective MTR causes HMAG Defective MTR causes methylmalonic aciduria and homocystinuria type cblG Defects in MTR cause methylcobalamin deficiency type G (cblG; MIM:250940), an autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria (Leclerc et al. 1996, Gulati et al. 1996, Watkins et al. 2002). Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective MTR does not transfer CH3 group from MTHF to cob(I)alamin Defective MTR does not transfer CH3 group from MTHF to cob(I)alamin Methionine synthase (MTR) catalyses the transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to homocysteine (HCYS) to then form methionine (L-Met). In the first step, MTR mediates the transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to cob(I)alamin (B12s, bound to the enzyme MTR) to form the cofactor methylcobalamin (MeCbl), the form that activates MTR (Leclerc et al. 1996).<br><br>Defects in MTR cause methylcobalamin deficiency type G (cblG, methionine synthase deficiency; MIM:250940), an autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria. Mutations causing cblG include P1173L, Ile881, H920D, R585*, E1204* and A1204P (Leclerc et al. 1996, Gulati et al. 1996, Watkins et al. 2002). Authored: Jassal, B, 2013-05-02 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-02 Reactome DB_ID: 200665 1 5-methyltetrahydrofolic acid [ChEBI:15641] 5-methyltetrahydrofolic acid ChEBI 15641 Reactome DB_ID: 9013303 1 MTRR:mutant MTR(cob(I)alamin) [cytosol] MTRR:mutant MTR(cob(I)alamin) Reactome DB_ID: 3149530 1 MTRR:FMN:FAD [cytosol] MTRR:FMN:FAD Reactome DB_ID: 29386 1 Reactome DB_ID: 2980987 1 UniProt:Q9UBK8 MTRR MTRR MTRR FUNCTION Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin (PubMed:17892308). Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species (Probable). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (PubMed:27771510). Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance (By similarity). Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme (PubMed:16769880). Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme (PubMed:16769880).SUBUNIT Forms a multiprotein complex with MMACHC, MMADHC AND MTR.TISSUE SPECIFICITY Found in all tissues tested, particularly abundant in skeletal muscle.MISCELLANEOUS It is debated whether the reduction of free aquacob(II)alamin occurs spontaneously or is enzyme catalyzed. 1 EQUAL 725 EQUAL Reactome DB_ID: 73524 1 Reactome Database ID Release 78 3149530 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3149530 Reactome R-HSA-3149530 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3149530.1 Reactome DB_ID: 9013301 1 mutant MTR:Zn2+:cob(I)alamin [cytosol] mutant MTR:Zn2+:cob(I)alamin Reactome DB_ID: 29426 1 Reactome DB_ID: 3149496 1 cob(I)alamin [ChEBI:15982] cob(I)alamin ChEBI 15982 Converted from EntitySet in Reactome Reactome DB_ID: 3321946 1 MTR mutants [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MTR H920D [cytosol] MTR Ile881 [cytosol] MTR P1173L [cytosol] MTR A410P [cytosol] MTR E1204* [cytosol] MTR R585* [cytosol] Reactome Database ID Release 78 9013301 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013301 Reactome R-HSA-9013301 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013301.1 Reactome Database ID Release 78 9013303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013303 Reactome R-HSA-9013303 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013303.1 Reactome Database ID Release 78 3321918 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3321918 Reactome R-HSA-3321918 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3321918.2 8968736 Pubmed 1996 Defects in human methionine synthase in cblG patients Gulati, S Baker, P Li, Y N Fowler, B Kruger, W Brody, L C Banerjee, R Hum. Mol. Genet. 5:1859-65 12068375 Pubmed 2002 Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L Watkins, D Ru, Ming Hwang, HY Kim, Caroline D Murray, Angus Philip, Noah S Kim, William Legakis, Helen Wai, Timothy Hilton, JF Ge, Bing Doré, Carole Hosack, Angela Wilson, Aaron Gravel, RA Shane, B Hudson, TJ Rosenblatt, DS Am. J. Hum. Genet. 71:143-53 8968737 Pubmed 1996 Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders Leclerc, D Campeau, E Goyette, P Adjalla, CE Christensen, B Ross, M Eydoux, P Rosenblatt, DS Rozen, R Gravel, RA Hum Mol Genet 5:1867-74 Defective MTR does not transfer CH3 group from MeCbl to HCYS Defective MTR does not transfer CH3 group from MeCbl to HCYS Methionine synthase (MTR) catalyses the transfer of a methyl group from 5-methyltetrahydrofolate (MTHF) to MTR-bound cob(I)alamin to form methylcobalamin (MeCbl). In the second step, the methyl group from MeCbl is transferred to homocysteine (HCYS), forming methionine (L-Met) (Leclerc et al. 1996). Under normal conditions, the enzyme-bound cobalamin shuttles between the cob(I)alamin and MeCbl forms. Every few hundred cycles, enzyme-bound cob(I)alamin is spontaneously oxidized to cob(II)alamin, inactivating MTR. Active MTR is regenerated by MTRR which, in conjunction with MTR, catalyzes reductive methylation of cob(II)alamin to MeCbl using SAM as a methyl donor.<br><br>Defects in MTR cause methylcobalamin deficiency type G (cblG, methionine synthase deficiency; MIM:250940), an autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria. Mutations causing cblG include P1173L, Ile881, H920D, R585*, E1204* and A1204P (Leclerc et al. 1996, Gulati et al. 1996, Watkins et al. 2002). Authored: Jassal, Bijay, 2013-05-03 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, Bijay, 2013-05-03 Reactome DB_ID: 174369 1 homocysteine [ChEBI:17230] homocysteine ChEBI 17230 Reactome DB_ID: 9013305 1 MTRR:mutant MTR(MeCbl) [cytosol] MTRR:mutant MTR(MeCbl) Reactome DB_ID: 3149530 1 Reactome DB_ID: 9013304 1 mutant MTR:Zn2+:MeCbl [cytosol] mutant MTR:Zn2+:MeCbl Reactome DB_ID: 29426 1 Reactome DB_ID: 3149508 1 methylcobalamin [ChEBI:28115] methylcobalamin CO-METHYLCOBALAMIN mecobalamin MeCbl ChEBI 28115 Converted from EntitySet in Reactome Reactome DB_ID: 3321946 1 Reactome Database ID Release 78 9013304 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013304 Reactome R-HSA-9013304 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013304.1 Reactome Database ID Release 78 9013305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9013305 Reactome R-HSA-9013305 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9013305.1 Reactome Database ID Release 78 3322140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3322140 Reactome R-HSA-3322140 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3322140.2 Reactome Database ID Release 78 3359469 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359469 Reactome R-HSA-3359469 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359469.2 Defective MMAB causes MMA, cblB type Defective MMAB causes MMA, cblB type Defective MMAB causes methylmalonic aciduria, cblB type Defects in MMAB cause methylmalonic aciduria type cblB (cblB aka methylmalonic aciduria type B or vitamin B12 responsive methylmalonicaciduria of cblB complementation type; MIM:251110). Affected individuals have methylmalonic aciduria and episodes of metabolic ketoacidosis, despite a functional methylmalonyl CoA mutase. In severe cases, newborns become severely acidotic and may die if acidosis is not treated promptly (Dobson et al. 2002). Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 2.5.1.17 Defective MMAB does not transfer adenosyl group from ATP to B12s Defective MMAB does not transfer adenosyl group from ATP to B12s Mitochondrial cob(I)yrinic acid a,c-diamide adenosyltransferase (MMAB) is an enzyme involved in the adenosylation of cobalamin. MMAB transfers an adenosyl group from ATP to cob(I)alamin (B12s) to form adenosylcabalamin (AdoCbl) (Fan & Bobik 2008, Leal et al. 2003).<br><br>Defects in MMAB cause methylmalonic aciduria type cblB (cblB aka methylmalonic aciduria type B or vitamin B12-responsive methylmalonicaciduria of cblB complementation type; MIM:251110). Affected individuals have methylmalonic aciduria and episodes of metabolic ketoacidosis, despite a functional methylmalonyl CoA mutase. In severe cases, newborns become severely acidotic and may die if acidosis is not treated promptly (Dobson et al. 2002). The point mutations R186W, R191W and E193K result in very low levels of AdoCbl (Dobson et al. 2002). Authored: Jassal, Bijay, 2013-05-03 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, Bijay, 2013-05-03 Reactome DB_ID: 113593 1 mitochondrial matrix GO 0005759 Reactome DB_ID: 3159260 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3322148 MMAB mutants [mitochondrial matrix] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMAB E193K [mitochondrial matrix] MMAB R186W [mitochondrial matrix] MMAB R191W [mitochondrial matrix] UniProt Q96EY8 GO 0008817 GO molecular function Reactome Database ID Release 78 9631893 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9631893 Reactome Database ID Release 78 3322125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3322125 Reactome R-HSA-3322125 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3322125.2 12438653 Pubmed 2002 Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements Dobson, C Melissa Wai, Timothy Leclerc, Daniel Wilson, Aaron Wu, Xuchu Doré, Carole Hudson, Thomas Rosenblatt, DS Gravel, RA Proc. Natl. Acad. Sci. U.S.A. 99:15554-9 18251506 Pubmed 2008 Functional characterization and mutation analysis of human ATP:Cob(I)alamin adenosyltransferase Fan, Chenguang Bobik, TA Biochemistry 47:2806-13 12514191 Pubmed 2003 Identification of the human and bovine ATP:Cob(I)alamin adenosyltransferase cDNAs based on complementation of a bacterial mutant Leal, Nicole A Park, Sanghee D Kima, Peter E Bobik, TA J. Biol. Chem. 278:9227-34 Reactome Database ID Release 78 3359471 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359471 Reactome R-HSA-3359471 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359471.2 12471062 Pubmed 2002 Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria Dobson, C Melissa Wai, Timothy Leclerc, Daniel Kadir, Hakan Narang, Monica Lerner-Ellis, Jordan P Hudson, TJ Rosenblatt, DS Gravel, RA Hum. Mol. Genet. 11:3361-9 Defective MMAA causes MMA, cblA type Defective MMAA causes MMA, cblA type Defective MMAA causes methylmalonic aciduria, cblA type Defects in MMAA cause methylmalonic aciduria type cblA (cblA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonic aciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004). Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 Defective MMAA does not protect MUT Defective MMAA does not protect MUT Methylmalonic aciduria type A protein (MMAA) is thought to act as a chaperone to MUT, the enzyme which utilises adenosylcobalamin (AdoCbl) as a cofactor. MMAA is suggested to play a dual role with regards to MUT protection and reactivation. Some AdoCbl-dependent enzymes undergo suicide inactivation after catalysis due to the oxidative inactivation of Cbl. MMAA is thought to play a protective role to prevent MUT being inactivated in this way. Defects in MMAA cause methylmalonic aciduria type cblA (cblA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood. Mutations causing cblA include MMAA Q95*, R145*, Y207C and D87Ifs*11 (Dobson et al. 2002, Lerner-Ellis et al. 2004). Authored: Jassal, Bijay, 2013-05-03 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, Bijay, 2013-05-03 Reactome DB_ID: 5654974 1 2xMMAA mutants:2xMUT [mitochondrial matrix] 2xMMAA mutants:2xMUT Reactome DB_ID: 3159252 1 2xMUT [mitochondrial matrix] 2xMUT MUT dimer apoenzyme methylmalonyl-CoA mutase, homodimer Reactome DB_ID: 70998 2 UniProt:P22033 MMUT MMUT MMUT MUT FUNCTION Catalyzes the reversible isomerization of methylmalonyl-CoA (MMCoA) (generated from branched-chain amino acid metabolism and degradation of dietary odd chain fatty acids and cholesterol) to succinyl-CoA (3-carboxypropionyl-CoA), a key intermediate of the tricarboxylic acid cycle.ACTIVITY REGULATION During catalysis, accumulation of oxidized inactive cofactor hydroxocobalamin (OH2Cbl) leads to loss of MMUT activity (PubMed:21138732, PubMed:28943303). Interaction with MMAA decreases the rate of OH2Cbl formation and promotes the replacement of OH2Cbl by the active cofactor adenosylcobalamin (AdoCbl), thereby restoring MMUT activity (PubMed:21138732, PubMed:28943303). Inhibited by itaconyl-CoA, a metabolite that inactivates the coenzyme B12 cofactor (PubMed:29056341). Inhibited at high concentration of substrate (PubMed:28943303).SUBUNIT Homodimer (PubMed:20876572). Interacts (the apoenzyme form) with MMAA; the interaction is GTP dependent (PubMed:20876572, PubMed:21138732, PubMed:28943303).SIMILARITY Belongs to the methylmalonyl-CoA mutase family. UniProt P22033 33 EQUAL 750 EQUAL Reactome Database ID Release 78 3159252 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3159252 Reactome R-HSA-3159252 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3159252.1 Converted from EntitySet in Reactome Reactome DB_ID: 3322146 2 MMAA mutants [mitochondrial matrix] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMAA R145* [mitochondrial matrix] MMAA Y207C [mitochondrial matrix] MMAA K88Ifs*9 [mitochondrial matrix] MMAA Q95* [mitochondrial matrix] UniProt Q8IVH4 Reactome Database ID Release 78 5654974 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5654974 Reactome R-HSA-5654974 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5654974.2 Reactome DB_ID: 3159297 1 cobamamide [ChEBI:18408] cobamamide ChEBI 18408 Reactome Database ID Release 78 3322135 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3322135 Reactome R-HSA-3322135 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3322135.2 16281286 Pubmed 2006 Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype Worgan, Lisa C Niles, Kirsten Tirone, Jamie C Hofmann, Adam Verner, Andrei Sammak, Alya'a Kucic, Terrence Lepage, Pierre Rosenblatt, DS Hum. Mutat. 27:31-43 21138732 Pubmed 2011 Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein Takahashi-Íñiguez, Tóshiko García-Arellano, Humberto Trujillo-Roldán, Mauricio A Flores, María Elena Biochem. Biophys. Res. Commun. 404:443-7 2567699 Pubmed 1989 Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction Jansen, R Kalousek, F Fenton, W A Rosenberg, L E Ledley, FD Genomics 4:198-205 20876572 Pubmed 2010 Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation Froese, D Sean Kochan, Grazyna Muniz, João R C Wu, Xuchu Gileadi, Carina Ugochukwu, Emelie Krysztofinska, Ewelina Gravel, RA Oppermann, U Yue, Wyatt W J. Biol. Chem. 285:38204-13 16866376 Pubmed 2006 Assembly and protection of the radical enzyme, methylmalonyl-CoA mutase, by its chaperone Padovani, Dominique Banerjee, Ruma Biochemistry 45:9300-6 15523652 Pubmed 2004 Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism Lerner-Ellis, Jordan P Dobson, C Melissa Wai, Timothy Watkins, D Tirone, Jamie C Leclerc, Daniel Doré, Carole Lepage, Pierre Gravel, RA Rosenblatt, DS Hum. Mutat. 24:509-16 Reactome Database ID Release 78 3359475 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3359475 Reactome R-HSA-3359475 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3359475.2 Defective MUT causes MMAM Defective MUT causes MMAM Defective MUT causes methylmalonic aciduria mut type Defects in MUT cause methylmalonic aciduria, mut type (MMAM; MIM:251000), an often fatal disorder of organic acid metabolism (Worgan et al. 2006). Authored: Jassal, B, 2013-05-13 Reviewed: Watkins, D, 2013-08-14 Edited: Jassal, B, 2013-05-13 5.4.99.2 Defective MUT does not isomerise L-MM-CoA to SUCC-CoA Defective MUT does not isomerise L-MM-CoA to SUCC-CoA Methylmalonyl CoA mutase (MUT aka MCM) (Jansen et al. 1989) utilises adenosylcobalamin (AdoCbl) as a cofactor catalyzes interchange of a carbonylCoA group and a hydrogen atom in conversion of methylmalonyl CoA to form succinyl CoA, a precursor for the citric acid cycle. MUT has a homodimeric structure and is located in the mitochondrial matrix. Defects in MUT cause methylmalonic aciduria, mut type (MMAM; MIM:251000), an often fatal disorder of organic acid metabolism (Worgan et al. 2006). Patients with no residual MUT activity are defined as MMA mut(0); those with some residual MUT activity are defined as MMA mut(-). Mutations causing MMA mut(0) type of disorder include Q17*, W105R, A378E, R93H, G623R, G703R, N219Y, R108C and G215S (Ledley et al. 1990, Jansen & Ledley 1990, Raff et al 1991, Ledley & Rosenblatt 1997, Qureshi et al. 1994, Acquaviva et al. 2001, Acquaviva et al. 2005, Berger et al. 2001, Worgan et al. 2006, Cavicchi et al. 2006).