BioPAX pathway converted from "Diseases of metabolism" in the Reactome database. 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 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 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 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 LEFT-TO-RIGHT 3.2.1.76 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 Heparan sulfate chain(6) 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 DB_ID: 2090055 lysosomal lumen GENE ONTOLOGY 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 ChEBI CHEBI:63809 Reactome Database ID Release 78 2090055 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=2090055 Reactome R-ALL-2090055 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-ALL-2090055.3 Reactome http://www.reactome.org H2O water Reactome DB_ID: 1605715 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 1605715 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=1605715 Reactome R-ALL-1605715 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-ALL-1605715.3 COMPOUND C00001 additional information MI MI:0361 ACTIVATION Converted from EntitySet in Reactome IDUA mutants Reactome DB_ID: 2207701 IDUA P553R Alpha-L-iduronidase IDUA_HUMAN p.P553R-IDUA Reactome DB_ID: 2207700 UniProt:P35475 IDUA IDUA SUBUNIT Monomer.TISSUE SPECIFICITY Ubiquitous.PTM N-glycosylation at Asn-372 contributes to substrate binding and is required for full enzymatic activity.SIMILARITY Belongs to the glycosyl hydrolase 39 family. Homo sapiens NCBI Taxonomy 9606 UniProt P35475 533 EQUAL L-proline removal MOD MOD:01645 28 EQUAL 653 EQUAL Reactome Database ID Release 78 2207700 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=2207700 Reactome R-HSA-2207700 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-2207700.1 IDUA Q70* Alpha-L-iduronidase IDUA_HUMAN p.Gln70Ter IDUA Reactome DB_ID: 2207687 70 EQUAL L-glutamine removal MOD MOD:01637 28 EQUAL 653 EQUAL Reactome Database ID Release 78 2207687 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=2207687 Reactome R-HSA-2207687 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-2207687.1 IDUA W402* Alpha-L-iduronidase IDUA_HUMAN p.Trp402Ter IDUA Reactome DB_ID: 2207692 402 EQUAL L-tryptophan removal MOD MOD:01648 28 EQUAL 653 EQUAL Reactome Database ID Release 78 2207692 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=2207692 Reactome R-HSA-2207692 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-2207692.1 Reactome Database ID Release 78 2207701 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=2207701 Reactome R-HSA-2207701 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-2207701.1 GENE ONTOLOGY GO:0003940 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity 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 LEFT-TO-RIGHT 3.2.1.76 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 IdoA-GalNAc(4S)-GlcA-Gal-Gal-Xyl 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 Reactome DB_ID: 2105025 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 CHEBI:63873 Reactome Database ID Release 78 2105025 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=2105025 Reactome R-ALL-2105025 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-ALL-2105025.3 ACTIVATION 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 LEFT-TO-RIGHT 3.2.1.76 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 Heparan sulfate chain(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 Reactome DB_ID: 2090033 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 CHEBI:63666 Reactome Database ID Release 78 2090033 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=2090033 Reactome R-ALL-2090033 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-ALL-2090033.3 ACTIVATION 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 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 LEFT-TO-RIGHT 3.1.6.13 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 ChEBI:63517 chain 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 Reactome DB_ID: 2065213 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 CHEBI:63517 Reactome Database ID Release 78 2065213 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=2065213 Reactome R-ALL-2065213 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-ALL-2065213.3 ACTIVATION Ca2+:Ca2+:IDS mutants:IDS mutants Reactome DB_ID: 9631735 Ca2+ Calcium calcium(2+) Reactome DB_ID: 1606834 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 78 1606834 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=1606834 Reactome R-ALL-1606834 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-ALL-1606834.3 COMPOUND C00076 2 Converted from EntitySet in Reactome IDS mutants Reactome DB_ID: 2210362 IDS_HUMAN IDS (34-455) R443* Iduronate 2-sulfatase 42kDa R443* p.Arg443Ter IDS Reactome DB_ID: 2210360 UniProt:P22304 IDS IDS SIDS FUNCTION Lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate.SUBUNIT Monomer (PubMed:28593992). The 58-kDa mature form is composed of two chains resulting from proteolitic processing, the 42-kDa chain and the 14-kDa chain that remain stably associated and form the 58-kDa intermediate form which is enzymatically active (PubMed:28593992).TISSUE SPECIFICITY Liver, kidney, lung, and placenta.PTM Synthesized as a 75-kDa precursor form in the endoplasmic reticulum (ER), and then processed by proteolytic cleavage through various intermediates to yield a 55-kDa mature form, with the release of an 18 kDa polypeptide.PTM The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity.SIMILARITY Belongs to the sulfatase family. UniProt P22304 443 EQUAL L-arginine removal MOD MOD:01632 34 EQUAL 455 EQUAL Reactome Database ID Release 78 2210360 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=2210360 Reactome R-HSA-2210360 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-2210360.1 IDS_HUMAN IDS (456-550) R468Q Iduronate 2-sulfatase 14kDa R468Q p.Arg468Gln IDS Reactome DB_ID: 2457604 468 EQUAL 456 EQUAL 550 EQUAL Reactome Database ID Release 78 2457604 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=2457604 Reactome R-HSA-2457604 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-2457604.1 IDS_HUMAN IDS (456-550) R468L Iduronate 2-sulfatase 14kDa R468L p.Arg468Leu IDS Reactome DB_ID: 2210364 468 EQUAL 456 EQUAL 550 EQUAL Reactome Database ID Release 78 2210364 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=2210364 Reactome R-HSA-2210364 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-2210364.1 IDS_HUMAN IDS (456-550) R468W Iduronate 2-sulfatase 14kDa R468W p.Arg468Trp IDS Reactome DB_ID: 2210368 468 EQUAL 456 EQUAL 550 EQUAL Reactome Database ID Release 78 2210368 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=2210368 Reactome R-HSA-2210368 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-2210368.1 Reactome Database ID Release 78 2210362 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=2210362 Reactome R-HSA-2210362 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-2210362.1 2 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 GENE ONTOLOGY GO:0004423 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 LEFT-TO-RIGHT 3.1.6.13 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 Heparan sulfate chain(5) 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 Reactome DB_ID: 2090080 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 CHEBI:63808 Reactome Database ID Release 78 2090080 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=2090080 Reactome R-ALL-2090080 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-ALL-2090080.3 ACTIVATION 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 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 LEFT-TO-RIGHT 3.10.1.1 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 Heparan sulfate chain(7) 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 DB_ID: 2090070 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 CHEBI:63810 Reactome Database ID Release 78 2090070 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=2090070 Reactome R-ALL-2090070 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-ALL-2090070.3 2 ACTIVATION Converted from EntitySet in Reactome SGSH mutants Reactome DB_ID: 2214337 SPHM_HUMAN SGSH C1091del N-sulphoglucosamine sulphohydrolase p.Cys1091del SGSH Reactome DB_ID: 2214344 UniProt:P51688 SGSH SGSH HSS FUNCTION Catalyzes a step in lysosomal heparan sulfate degradation.PTM The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity.SIMILARITY Belongs to the sulfatase family. UniProt P51688 Deletion of residues 1091 to 1091 21 EQUAL 502 EQUAL Reactome Database ID Release 78 2214344 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=2214344 Reactome R-HSA-2214344 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-2214344.2 SGSH R245H N-sulphoglucosamine sulphohydrolase SPHM_HUMAN p.Arg245His SGSH Reactome DB_ID: 2214347 245 EQUAL 21 EQUAL 502 EQUAL Reactome Database ID Release 78 2214347 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=2214347 Reactome R-HSA-2214347 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-2214347.1 SGSH R74C N-sulphoglucosamine sulphohydrolase SPHM_HUMAN p.Arg74Cys SGSH Reactome DB_ID: 2214341 74 EQUAL 21 EQUAL 502 EQUAL Reactome Database ID Release 78 2214341 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=2214341 Reactome R-HSA-2214341 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-2214341.1 SGSH S66W N-sulphoglucosamine sulphohydrolase SPHM_HUMAN p.Ser66Trp SGSH Reactome DB_ID: 2214340 66 EQUAL L-serine removal MOD MOD:01646 21 EQUAL 502 EQUAL Reactome Database ID Release 78 2214340 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=2214340 Reactome R-HSA-2214340 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-2214340.1 Reactome Database ID Release 78 2214337 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=2214337 Reactome R-HSA-2214337 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-2214337.1 GENE ONTOLOGY GO:0016250 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 LEFT-TO-RIGHT 3.10.1.1 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 Heparan sulfate chain(2) 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 Reactome DB_ID: 2090072 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 CHEBI:63805 Reactome Database ID Release 78 2090072 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=2090072 Reactome R-ALL-2090072 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-ALL-2090072.3 2 ACTIVATION 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 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 LEFT-TO-RIGHT 3.2.1.50 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 Heparan sulfate chain(4) 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 Reactome DB_ID: 2090069 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 CHEBI:63807 Reactome Database ID Release 78 2090069 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=2090069 Reactome R-ALL-2090069 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-ALL-2090069.3 ACTIVATION Converted from EntitySet in Reactome NAGLU mutants Reactome DB_ID: 2219572 ANAG_HUMAN NAGLU R297* Alpha-N-acetylglucosaminidase NAGLU 77kDa form p.Arg297Ter NAGLU mutant Reactome DB_ID: 2219553 UniProt:P54802 NAGLU NAGLU UFHSD1 FUNCTION Involved in the degradation of heparan sulfate.SUBUNIT Monomer and homodimer.TISSUE SPECIFICITY Liver, ovary, peripheral blood leukocytes, testis, prostate, spleen, colon, lung, placenta and kidney.SIMILARITY Belongs to the glycosyl hydrolase 89 family.CAUTION A MPS3B mutation at position 100 was erroneously reported (PubMed:9950362) as an amino acid change from Arg to His. The right amino acid change is from His to Arg. UniProt P54802 297 EQUAL 59 EQUAL 743 EQUAL Reactome Database ID Release 78 2219553 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=2219553 Reactome R-HSA-2219553 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-2219553.1 ANAG_HUMAN NAGLU R626* Alpha-N-acetylglucosaminidase NAGLU 77kDa form p.Arg626Ter NAGLU mutant Reactome DB_ID: 2219568 626 EQUAL 59 EQUAL 743 EQUAL Reactome Database ID Release 78 2219568 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=2219568 Reactome R-HSA-2219568 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-2219568.1 ANAG_HUMAN NAGLU R674C Alpha-N-acetylglucosaminidase NAGLU 77kDa form p.Arg674Cys NAGLU mutant Reactome DB_ID: 2219558 674 EQUAL 59 EQUAL 743 EQUAL Reactome Database ID Release 78 2219558 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=2219558 Reactome R-HSA-2219558 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-2219558.1 ANAG_HUMAN NAGLU R674H Alpha-N-acetylglucosaminidase NAGLU 77kDa form p.Arg674His NAGLU mutant Reactome DB_ID: 2219557 674 EQUAL 59 EQUAL 743 EQUAL Reactome Database ID Release 78 2219557 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=2219557 Reactome R-HSA-2219557 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-2219557.1 Reactome Database ID Release 78 2219572 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=2219572 Reactome R-HSA-2219572 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-2219572.1 GENE ONTOLOGY GO:0004561 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 LEFT-TO-RIGHT 3.2.1.50 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 Heparan chain(2) 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 Reactome DB_ID: 2090053 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 CHEBI:63645 Reactome Database ID Release 78 2090053 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=2090053 Reactome R-ALL-2090053 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-ALL-2090053.3 ACTIVATION 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 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 LEFT-TO-RIGHT 2.3.1.78 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 Heparan chain(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 Reactome DB_ID: 2090045 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 CHEBI:63811 Reactome Database ID Release 78 2090045 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=2090045 Reactome R-ALL-2090045 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-ALL-2090045.3 Ac-CoA Acetyl coenzyme A acetyl-CoA acetyl-CoA(4-) Reactome DB_ID: 76183 cytosol GENE ONTOLOGY GO:0005829 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) acetyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-coenzyme A(4-) acetyl-CoA tetraanion AcCoA(4-) ChEBI CHEBI:57288 Reactome Database ID Release 78 76183 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=76183 Reactome R-ALL-76183 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-ALL-76183.4 COMPOUND C00024 ACTIVATION Converted from EntitySet in Reactome HGSNAT mutants Reactome DB_ID: 2245239 HGNAT_HUMAN HGSNAT R344C Heparan-alpha-glucosaminide N-acetyltransferase p.Arg344Cys HGSNAT mutant Reactome DB_ID: 2245233 lysosomal membrane GENE ONTOLOGY GO:0005765 UniProt:Q68CP4 HGSNAT HGSNAT TMEM76 FUNCTION Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.SUBUNIT Homooligomer. Homooligomerization is necessary for enzyme activity.TISSUE SPECIFICITY Widely expressed, with highest level in leukocytes, heart, liver, skeletal muscle, lung, placenta and liver.PTM Undergoes intralysosomal proteolytic cleavage; occurs within the end of the first and/or the beginning of the second luminal domain and is essential for the activation of the enzyme.PTM Glycosylated.MISCELLANEOUS A signal sequence is predicted but has been shown not to be cleaved in the reticulum endoplasmic. UniProt Q68CP4 344 EQUAL 1 EQUAL 663 EQUAL Reactome Database ID Release 78 2245233 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=2245233 Reactome R-HSA-2245233 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-2245233.1 HGNAT_HUMAN HGSNAT R384* Heparan-alpha-glucosaminide N-acetyltransferase p.Arg384Ter HGSNAT mutant Reactome DB_ID: 2245250 384 EQUAL 1 EQUAL 663 EQUAL Reactome Database ID Release 78 2245250 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=2245250 Reactome R-HSA-2245250 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-2245250.1 HGNAT_HUMAN HGSNAT S518F Heparan-alpha-glucosaminide N-acetyltransferase p.Ser518Phe HGSNAT mutant Reactome DB_ID: 2245230 518 EQUAL 1 EQUAL 663 EQUAL Reactome Database ID Release 78 2245230 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=2245230 Reactome R-HSA-2245230 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-2245230.1 HGNAT_HUMAN W403C/A615T-HGSNAT Heparan-alpha-glucosaminide N-acetyltransferase p.Trp403Cys/p.Ala615Thr HGSNAT mutant Reactome DB_ID: 2245245 403 EQUAL 615 EQUAL L-alanine removal MOD MOD:01631 1 EQUAL 663 EQUAL Reactome Database ID Release 78 2245245 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=2245245 Reactome R-HSA-2245245 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-2245245.1 Reactome Database ID Release 78 2245239 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=2245239 Reactome R-HSA-2245239 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-2245239.1 GENE ONTOLOGY GO:0015019 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 LEFT-TO-RIGHT 2.3.1.78 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 Heparan sulfate chain(3) 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 Reactome DB_ID: 2090040 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 CHEBI:63806 Reactome Database ID Release 78 2090040 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=2090040 Reactome R-ALL-2090040 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-ALL-2090040.3 ACTIVATION 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 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 LEFT-TO-RIGHT 3.1.6.14 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 GlcNAc(S)-Gal-GlcNAc(S)-Gal beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp Reactome DB_ID: 2104995 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 CHEBI:63851 Reactome Database ID Release 78 2104995 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=2104995 Reactome R-ALL-2104995 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-ALL-2104995.3 KEGG Glycan G06780 ACTIVATION Converted from EntitySet in Reactome GNS mutants Reactome DB_ID: 2245240 GNS Q272* N-acetylglucosamine-6-sulfatase GNS_HUMAN p.Gln272Ter GNS mutant Reactome DB_ID: 2245247 UniProt:P15586 GNS GNS PTM The form A (78 kDa) is processed by internal peptidase cleavage to a 32 kDa N-terminal species (form B) and a 48 kDa C-terminal species.PTM The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity.SIMILARITY Belongs to the sulfatase family. UniProt P15586 272 EQUAL 37 EQUAL 552 EQUAL Reactome Database ID Release 78 2245247 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=2245247 Reactome R-HSA-2245247 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-2245247.1 GNS Q390* N-acetylglucosamine-6-sulfatase GNS_HUMAN p.Gln390Ter GNS mutant Reactome DB_ID: 2245231 390 EQUAL 37 EQUAL 552 EQUAL Reactome Database ID Release 78 2245231 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=2245231 Reactome R-HSA-2245231 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-2245231.1 GNS R355* N-acetylglucosamine-6-sulfatase GNS_HUMAN p.Arg355Ter GNS mutant Reactome DB_ID: 2245238 355 EQUAL 37 EQUAL 552 EQUAL Reactome Database ID Release 78 2245238 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=2245238 Reactome R-HSA-2245238 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-2245238.1 GNS S94I N-acetylglucosamine-6-sulfatase HUMAN GNS p.Ser94Ile GNS mutant Reactome DB_ID: 2245243 94 EQUAL 37 EQUAL 552 EQUAL Reactome Database ID Release 78 2245243 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=2245243 Reactome R-HSA-2245243 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-2245243.1 Reactome Database ID Release 78 2245240 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=2245240 Reactome R-HSA-2245240 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-2245240.1 GENE ONTOLOGY GO:0008449 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 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 LEFT-TO-RIGHT 3.1.6.4 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 Gal(S)-GlcNAc(S)-Gal-GlcNAc(S)-Gal beta-D-Galp6S-(1->4)-beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp Reactome DB_ID: 2105007 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 CHEBI:63846 Reactome Database ID Release 78 2105007 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=2105007 Reactome R-ALL-2105007 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-ALL-2105007.3 KEGG Glycan G13031 ACTIVATION Converted from EntitySet in Reactome GALNS mutants Reactome DB_ID: 2245328 GALNS G301C N-acetylgalactosamine-6-sulfatase GALNS_HUMAN p.Gly301Cys GALNS Reactome DB_ID: 2245324 UniProt:P34059 GALNS GALNS SUBUNIT Homodimer.PTM The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity.SIMILARITY Belongs to the sulfatase family. UniProt P34059 301 EQUAL glycine removal MOD MOD:01638 27 EQUAL 522 EQUAL Reactome Database ID Release 78 2245324 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=2245324 Reactome R-HSA-2245324 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-2245324.1 GALNS I113F N-acetylgalactosamine-6-sulfatase GALNS_HUMAN p.Ile113Phe GALNS mutant Reactome DB_ID: 2245331 113 EQUAL L-isoleucine removal MOD MOD:01640 27 EQUAL 522 EQUAL Reactome Database ID Release 78 2245331 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=2245331 Reactome R-HSA-2245331 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-2245331.1 GALNS R386C N-acetylgalactosamine-6-sulfatase GALNS_HUMAN p.Arg386Cys GALNS mutant Reactome DB_ID: 2245326 386 EQUAL 27 EQUAL 522 EQUAL Reactome Database ID Release 78 2245326 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=2245326 Reactome R-HSA-2245326 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-2245326.1 Reactome Database ID Release 78 2245328 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=2245328 Reactome R-HSA-2245328 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-2245328.1 GENE ONTOLOGY GO:0043890 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 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 LEFT-TO-RIGHT 3.2.1.23 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 Gal-GlcNAc(S)-Gal-GlcNAc(S)-Gal beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-beta-D-Galp-(1->4)-beta-D-GlcpNAc6S-(1->3)-D-Galp Reactome DB_ID: 2104997 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 CHEBI:63850 Reactome Database ID Release 78 2104997 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=2104997 Reactome R-ALL-2104997 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-ALL-2104997.3 KEGG Glycan G13032 ACTIVATION Converted from EntitySet in Reactome GLB1 mutants Reactome DB_ID: 2262737 GLB1 R482C Beta-galactosidase BGAL_HUMAN p.Arg482Cys GLB1 Reactome DB_ID: 2262739 UniProt:P16278 GLB1 GLB1 ELNR1 SUBUNIT Homodimer (PubMed:22128166). May form higher multimers (Probable).TISSUE SPECIFICITY Detected in placenta (at protein level) (PubMed:8383699). Detected in fibroblasts and testis (PubMed:2511208).SIMILARITY Belongs to the glycosyl hydrolase 35 family. UniProt P16278 482 EQUAL 29 EQUAL 677 EQUAL Reactome Database ID Release 78 2262739 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=2262739 Reactome R-HSA-2262739 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-2262739.1 GLB1 W273L Beta-galactosidase BGAL_HUMAN p.Trp273Leu GLB1 Reactome DB_ID: 2262738 273 EQUAL 29 EQUAL 677 EQUAL Reactome Database ID Release 78 2262738 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=2262738 Reactome R-HSA-2262738 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-2262738.1 GLB1 W509C Beta-galactosidase BGAL_HUMAN p.Try509Cys GLB1 Reactome DB_ID: 2262732 509 EQUAL 29 EQUAL 677 EQUAL Reactome Database ID Release 78 2262732 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=2262732 Reactome R-HSA-2262732 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-2262732.1 GLB1 Y83C Beta-galactosidase BGAL_HUMAN p.Tyr83Cys GLB1 Reactome DB_ID: 2262735 83 EQUAL L-tyrosine removal MOD MOD:01649 29 EQUAL 677 EQUAL Reactome Database ID Release 78 2262735 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=2262735 Reactome R-HSA-2262735 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-2262735.1 Reactome Database ID Release 78 2262737 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=2262737 Reactome R-HSA-2262737 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-2262737.1 GENE ONTOLOGY GO:0004565 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 LEFT-TO-RIGHT 3.2.1.23 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 linker chain(2) Gal-Gal-Xyl- chain beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group Reactome DB_ID: 2090075 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 CHEBI:63503 Reactome Database ID Release 78 2090075 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=2090075 Reactome R-ALL-2090075 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-ALL-2090075.3 2 ACTIVATION 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 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 LEFT-TO-RIGHT 3.1.6.12 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 Converted from EntitySet in Reactome C4S/C6S chains Reactome DB_ID: 2065251 C4S chain Chondroitin 4-sulfate chain beta-D-GalNAc-(1->4)-beta-D-GlcA-(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 Reactome DB_ID: 2065210 beta-D-GalNAc-(1->4)-beta-D-GlcA-(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:63513] beta-D-GalNAc-(1->4)-beta-D-GlcA-(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 CHEBI:63513 Reactome Database ID Release 78 2065210 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=2065210 Reactome R-ALL-2065210 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-ALL-2065210.3 C6S chain Chondroitin 6-sulfate chain beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc6S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group Reactome DB_ID: 2065246 beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc6S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63512] beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc6S-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI CHEBI:63512 Reactome Database ID Release 78 2065246 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=2065246 Reactome R-ALL-2065246 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-ALL-2065246.3 Reactome Database ID Release 78 2065251 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=2065251 Reactome R-ALL-2065251 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-ALL-2065251.1 ACTIVATION ARSB mutants:Ca2+ Reactome DB_ID: 9631731 Converted from EntitySet in Reactome ARSB mutants Reactome DB_ID: 2314611 ARSB C117R Arylsulfatase B ARSB_HUMAN p.Cys117Arg ARSB Reactome DB_ID: 2314618 UniProt:P15848 ARSB ARSB FUNCTION Removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation (PubMed:19306108). Involved in the regulation of cell adhesion, cell migration and invasion in colonic epithelium (PubMed:19306108). In the central nervous system, is a regulator of neurite outgrowth and neuronal plasticity, acting through the control of sulfate glycosaminoglycans and neurocan levels (By similarity).ACTIVITY REGULATION Inhibited by ethanol (By similarity).SUBUNIT Monomer.PTM The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity. This post-translational modification is severely defective in multiple sulfatase deficiency (MSD).SIMILARITY Belongs to the sulfatase family. UniProt P15848 117 EQUAL L-cysteine removal MOD MOD:01635 37 EQUAL 533 EQUAL Reactome Database ID Release 78 2314618 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=2314618 Reactome R-HSA-2314618 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-2314618.1 ARSB G144R Arylsulfatase B ARSB_HUMAN p.Gly144Arg ARSB Reactome DB_ID: 2314612 144 EQUAL 37 EQUAL 533 EQUAL Reactome Database ID Release 78 2314612 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=2314612 Reactome R-HSA-2314612 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-2314612.1 ARSB P116H Arylsulfatase B ARSB_HUMAN p.Pro116His ARSB Reactome DB_ID: 2314619 116 EQUAL 37 EQUAL 533 EQUAL Reactome Database ID Release 78 2314619 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=2314619 Reactome R-HSA-2314619 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-2314619.1 ARSB R95Q Arylsulfatase B ARSB_HUMAN p.Arg95Gln/p.His393Pro ARSB Reactome DB_ID: 2314614 95 EQUAL 37 EQUAL 533 EQUAL Reactome Database ID Release 78 2314614 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=2314614 Reactome R-HSA-2314614 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-2314614.1 ARSB_HUMAN ARSB Y86del Arylsulfatase B p.Tyr86del ARSB Reactome DB_ID: 2314606 Deletion of residues 356 to 358 37 EQUAL 533 EQUAL Reactome Database ID Release 78 2314606 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=2314606 Reactome R-HSA-2314606 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-2314606.2 ARSB H393P Arylsulfatase B ARSB_HUMAN p.Arg95Gln/p.His393Pro ARSB Reactome DB_ID: 5649492 393 EQUAL L-histidine removal MOD MOD:01639 37 EQUAL 533 EQUAL Reactome Database ID Release 78 5649492 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=5649492 Reactome R-HSA-5649492 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-5649492.1 Reactome Database ID Release 78 2314611 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=2314611 Reactome R-HSA-2314611 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-2314611.1 1 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 GENE ONTOLOGY GO:0003943 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 LEFT-TO-RIGHT 3.1.6.12 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 ChEBI:63519 chain 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 Reactome DB_ID: 2065231 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 CHEBI:63519 Reactome Database ID Release 78 2065231 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=2065231 Reactome R-ALL-2065231 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-ALL-2065231.3 ACTIVATION 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 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 LEFT-TO-RIGHT 3.2.1.31 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 (HA)2 Hyaluronic acid Hyaluronan Reactome DB_ID: 2160866 Reactome Database ID Release 78 2160866 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=2160866 Reactome R-ALL-2160866 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-ALL-2160866.3 ChEBI 64024 ACTIVATION Converted from EntitySet in Reactome GUSB mutants Reactome DB_ID: 2318394 GUSB R356* Beta-glucuronidase BGLR_HUMAN p.Arg356Ter GUSB Reactome DB_ID: 2318372 UniProt:P08236 GUSB GUSB FUNCTION Plays an important role in the degradation of dermatan and keratan sulfates.ACTIVITY REGULATION Inhibited by L-aspartic acid.SUBUNIT Homotetramer.PTM N-linked glycosylated with 3 to 4 oligosaccharide chains.SIMILARITY Belongs to the glycosyl hydrolase 2 family. UniProt P08236 356 EQUAL 23 EQUAL 651 EQUAL Reactome Database ID Release 78 2318372 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=2318372 Reactome R-HSA-2318372 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-2318372.1 GUSB A354V Beta-glucuronidase BGLR_HUMAN p.Ala354Val GUSB Reactome DB_ID: 2318376 354 EQUAL 23 EQUAL 651 EQUAL Reactome Database ID Release 78 2318376 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=2318376 Reactome R-HSA-2318376 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-2318376.1 GUSB R611W Beta-glucuronidase BGLR_HUMAN Arg611Trp GUSB Reactome DB_ID: 2318382 611 EQUAL 23 EQUAL 651 EQUAL Reactome Database ID Release 78 2318382 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=2318382 Reactome R-HSA-2318382 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-2318382.1 GUSB S52F Beta-glucuronidase BGLR_HUMAN p.Ser52Phel GUSB Reactome DB_ID: 2318391 52 EQUAL 23 EQUAL 651 EQUAL Reactome Database ID Release 78 2318391 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=2318391 Reactome R-HSA-2318391 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-2318391.1 GUSB R216W Beta-glucuronidase BGLR_HUMAN p.Arg216Try GUSB Reactome DB_ID: 2318584 216 EQUAL 23 EQUAL 651 EQUAL Reactome Database ID Release 78 2318584 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=2318584 Reactome R-HSA-2318584 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-2318584.1 Reactome Database ID Release 78 2318394 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=2318394 Reactome R-HSA-2318394 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-2318394.1 GENE ONTOLOGY GO:0004566 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 LEFT-TO-RIGHT 3.2.1.31 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 GlcA-β1,3-GlcNAc beta-D-GlcpA-(1->3)-D-GlcpNAc Reactome DB_ID: 2162224 beta-D-GlcpA-(1->3)-D-GlcpNAc [ChEBI:64024] beta-D-GlcpA-(1->3)-D-GlcpNAc ChEBI CHEBI:64024 Reactome Database ID Release 78 2162224 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=2162224 Reactome R-ALL-2162224 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-ALL-2162224.4 ACTIVATION 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 LEFT-TO-RIGHT 3.2.1.31 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 CS/HS precursor GlcA-Gal-Gal-Xyl linker chain beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group Reactome DB_ID: 2065212 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 CHEBI:63505 Reactome Database ID Release 78 2065212 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=2065212 Reactome R-ALL-2065212 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-ALL-2065212.3 ACTIVATION 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 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 LEFT-TO-RIGHT 3.2.1.35 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 Chondroitin chains Reactome DB_ID: 2065257 ChEBI:63515 chain beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc4,6S2-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group Reactome DB_ID: 2065209 beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc4,6S2-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63515] beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc4,6S2-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI CHEBI:63515 Reactome Database ID Release 78 2065209 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=2065209 Reactome R-ALL-2065209 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-ALL-2065209.3 Chondroitin chain beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group Reactome DB_ID: 2065239 beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group [ChEBI:63511] beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-GalNAc-(1->4)-beta-D-GlcA-(1->3)-beta-D-Gal-(1->3)-beta-D-Gal-(1->4)-beta-D-Xyl-yl group ChEBI CHEBI:63511 Reactome Database ID Release 78 2065239 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=2065239 Reactome R-ALL-2065239 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-ALL-2065239.3 Reactome Database ID Release 78 2065257 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=2065257 Reactome R-ALL-2065257 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-ALL-2065257.1 ACTIVATION HYAL1 HYAL1 E268K/V251_V262delinsFRVA Q263fs*20 Hyaluronidase-1 HYAL1_HUMAN c.1361del37ins14/p.E268K HYAL1 Reactome DB_ID: 2318714 UniProt:Q12794 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 263 EQUAL 264 EQUAL 265 EQUAL 266 EQUAL L-valine removal MOD MOD:01650 267 EQUAL 268 EQUAL L-glutamic acid removal MOD MOD:01636 269 EQUAL 270 EQUAL L-phenylalanine removal MOD MOD:01644 271 EQUAL 272 EQUAL 273 EQUAL 274 EQUAL 275 EQUAL 276 EQUAL 277 EQUAL 22 EQUAL 277 EQUAL Reactome Database ID Release 78 2318714 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=2318714 Reactome R-HSA-2318714 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-2318714.2 GENE ONTOLOGY GO:0004415 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 LEFT-TO-RIGHT 3.2.1.35 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 (HA)50 Hyaluronic acid Hyaluronan Reactome DB_ID: 2160864 Reactome Database ID Release 78 2160864 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=2160864 Reactome R-ALL-2160864 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-ALL-2160864.3 ChEBI 64024 ACTIVATION 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 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 GSD 0 (muscle) Glycogen storage disease type 0 (muscle GYS1) 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 LEFT-TO-RIGHT 2.4.1.11 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 oligoGlc-GYG1:GYS1 R462* tetramer Reactome DB_ID: 9628615 Mg2+ Magnesium magnesium(2+) Mg++ Reactome DB_ID: 29926 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI CHEBI:18420 Reactome Database ID Release 78 29926 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=29926 Reactome R-ALL-29926 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-ALL-29926.5 COMPOUND C00305 1 oligo((1,4)-alpha-glucosyl) GYG1 oligo((1,4)-alpha-glucosyl) glycogenin-1 oligo((1,4)-alpha-glucosyl) GN-1 Reactome DB_ID: 70292 UniProt:P46976 GYG1 GYG1 GYG 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 195 EQUAL O4'-glucosyl-L-tyrosine MOD MOD:00166 2 EQUAL 350 EQUAL Reactome Database ID Release 78 70292 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=70292 Reactome R-HSA-70292 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-70292.1 2 GYS1 R462* glycogen synthase 1 R462* Glycogen (starch) synthase, muscle R462X Reactome DB_ID: 3828056 UniProt:P13807 GYS1 GYS1 GYS 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 3828056 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=3828056 Reactome R-HSA-3828056 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-3828056.1 2 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 UDP-Glc UDP-glucose UDP-D-glucose UDPglucose Reactome DB_ID: 29410 UDP-D-glucose [ChEBI:18066] UDP-D-glucose ChEBI CHEBI:18066 Reactome Database ID Release 78 29410 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=29410 Reactome R-ALL-29410 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-ALL-29410.3 COMPOUND C00029 8 ACTIVATION activeUnit: #Protein55 GENE ONTOLOGY GO:0004373 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 GYS1 glycogen synthase 1 Glycogen (starch) synthase, muscle Reactome DB_ID: 71565 2 EQUAL 737 EQUAL Reactome Database ID Release 78 71565 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=71565 Reactome R-HSA-71565 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-71565.1 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 GSD 0 Glycogen storage disease type 0 (liver GYS2) 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 LEFT-TO-RIGHT 2.4.1.11 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 oligoGlc-GYG2:GYS2 mutant tetramer Reactome DB_ID: 9628616 1 Converted from EntitySet in Reactome GYS2 mutants Reactome DB_ID: 3858509 GYS2 H446D glycogen synthase 2 H446D Glycogen (starch) synthase, liver H446D Reactome DB_ID: 3858519 UniProt:P54840 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. UniProt P54840 446 EQUAL 1 EQUAL 703 EQUAL Reactome Database ID Release 78 3858519 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=3858519 Reactome R-HSA-3858519 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-3858519.1 GYS2 N39S glycogen synthase 2 N39S Glycogen (starch) synthase, liver N39S Reactome DB_ID: 3858521 39 EQUAL L-asparagine removal MOD MOD:01633 1 EQUAL 703 EQUAL Reactome Database ID Release 78 3858521 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=3858521 Reactome R-HSA-3858521 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-3858521.1 Reactome Database ID Release 78 3858509 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=3858509 Reactome R-HSA-3858509 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-3858509.1 2 oligo((1,4)-alpha-glycosyl) GYG2 oligo((1,4)-alpha-glycosyl) glycogenin-2 oligo((1,4)-alpha-glycosyl) GN-2 Reactome DB_ID: 70289 UniProt:O15488 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 228 EQUAL 1 EQUAL 501 EQUAL Reactome Database ID Release 78 70289 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=70289 Reactome R-HSA-70289 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-70289.1 2 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 8 ACTIVATION 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 GSD Ia Glycogen storage disease type Ia (G6PC) 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 LEFT-TO-RIGHT 3.1.3.9 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 G6P alpha-D-glucose 6-phosphate(2-) alpha-D-glucose 6-phosphate Reactome DB_ID: 113782 endoplasmic reticulum lumen GENE ONTOLOGY GO:0005788 alpha-D-glucose 6-phosphate(2-) [ChEBI:58225] alpha-D-glucose 6-phosphate(2-) alpha-D-glucopyranose 6-phosphate alpha-D-glucose 6-phosphate dianion alpha-D-glucose 6-phosphate 6-O-phosphonato-alpha-D-glucopyranose ChEBI CHEBI:58225 Reactome Database ID Release 78 113782 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=113782 Reactome R-ALL-113782 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-ALL-113782.4 COMPOUND C00668 H2O water Reactome DB_ID: 113519 Reactome Database ID Release 78 113519 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=113519 Reactome R-ALL-113519 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-ALL-113519.3 COMPOUND C00001 ACTIVATION Converted from EntitySet in Reactome G6PC mutants Reactome DB_ID: 3274535 G6PC H119L glucose-6-phosphatase, catalytic H119L G-6-Pase H119L Reactome DB_ID: 3274553 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 UniProt:P35575 G6PC1 G6PC1 G6PC G6PT FUNCTION Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. Forms with the glucose-6-phosphate transporter (SLC37A4/G6PT) the complex responsible for glucose production in the terminal step of glycogenolysis and gluconeogenesis. Hence, it is the key enzyme in homeostatic regulation of blood glucose levels.PATHWAY Carbohydrate biosynthesis; gluconeogenesis.SIMILARITY Belongs to the glucose-6-phosphatase family. UniProt P35575 119 EQUAL 1 EQUAL 357 EQUAL Reactome Database ID Release 78 3274553 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=3274553 Reactome R-HSA-3274553 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-3274553.1 G6PC R170Q glucose-6-phosphatase, catalytic R170Q G-6-Pase R170Q Reactome DB_ID: 3274556 170 EQUAL 1 EQUAL 357 EQUAL Reactome Database ID Release 78 3274556 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=3274556 Reactome R-HSA-3274556 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-3274556.1 G6PC R83C glucose-6-phosphatase, catalytic R83C G-6-Pase R83C Reactome DB_ID: 3274529 83 EQUAL 1 EQUAL 357 EQUAL Reactome Database ID Release 78 3274529 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=3274529 Reactome R-HSA-3274529 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-3274529.1 Reactome Database ID Release 78 3274535 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=3274535 Reactome R-HSA-3274535 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-3274535.1 GENE ONTOLOGY GO:0004346 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 GSD Ib Glycogen storage disease type Ib (SLC37A4) 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 LEFT-TO-RIGHT 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 Pi Orthophosphate hydrogenphosphate Phosphate Reactome DB_ID: 113551 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 78 113551 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=113551 Reactome R-ALL-113551 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-ALL-113551.4 COMPOUND C00009 G6P alpha-D-glucose 6-phosphate alpha-D-glucose 6-phosphate(2-) Reactome DB_ID: 30537 Reactome Database ID Release 78 30537 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=30537 Reactome R-ALL-30537 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-ALL-30537.4 COMPOUND C00668 ACTIVATION Converted from EntitySet in Reactome SLC37A4 mutants Reactome DB_ID: 3229129 SLC37A4 G20D Glucose-6-phosphate translocase G20D G6PT1_HUMAN G20D Reactome DB_ID: 3229123 UniProt:O43826 SLC37A4 SLC37A4 G6PT G6PT1 PRO0685 TRG19 FUNCTION Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum. Transports cytoplasmic glucose-6-phosphate into the lumen of the endoplasmic reticulum and translocates inorganic phosphate into the opposite direction. Forms with glucose-6-phosphatase the complex responsible for glucose production through glycogenolysis and gluconeogenesis. Hence, it plays a central role in homeostatic regulation of blood glucose levels.ACTIVITY REGULATION Inhibited by vanadate and chlorogenic acid.TISSUE SPECIFICITY Mostly expressed in liver and kidney.SIMILARITY Belongs to the major facilitator superfamily. Organophosphate:Pi antiporter (OPA) (TC 2.A.1.4) family. UniProt O43826 20 EQUAL 1 EQUAL 429 EQUAL Reactome Database ID Release 78 3229123 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=3229123 Reactome R-HSA-3229123 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-3229123.1 SLC37A4 G88D Glucose-6-phosphate translocase G88D G6PT1_HUMAN G88D Reactome DB_ID: 3229135 88 EQUAL 1 EQUAL 429 EQUAL Reactome Database ID Release 78 3229135 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=3229135 Reactome R-HSA-3229135 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-3229135.1 Reactome Database ID Release 78 3229129 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=3229129 Reactome R-HSA-3229129 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-3229129.1 GENE ONTOLOGY GO:0061513 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 GSD II Glycogen storage disease type II (GAA) 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 LEFT-TO-RIGHT 3.2.1.20 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 glycogen-GYG1 dimer Reactome DB_ID: 9036726 glycogen-GYG1 glycogen-glycogenin-1 Reactome DB_ID: 9036728 195 EQUAL 2 EQUAL 350 EQUAL Reactome Database ID Release 78 9036728 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=9036728 Reactome R-HSA-9036728 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-9036728.1 2 Mn2+ Manganese manganese(2+) Mn(II) Reactome DB_ID: 5357557 manganese(2+) [ChEBI:29035] manganese(2+) Mn(2+) MANGANESE (II) ION manganese, ion (Mn2+) manganese(II) manganous ion ChEBI CHEBI:29035 Reactome Database ID Release 78 5357557 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=5357557 Reactome R-ALL-5357557 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-ALL-5357557.3 COMPOUND C00034 1 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 2 ACTIVATION Converted from EntitySet in Reactome GAA mutants Reactome DB_ID: 5357599 GAA E521K lysosomal alpha-glucosidase E521K acid maltase E521K Reactome DB_ID: 5357598 UniProt:P10253 GAA GAA FUNCTION Essential for the degradation of glycogen in lysosomes (PubMed:1856189, PubMed:7717400, PubMed:14695532, PubMed:18429042). Has highest activity on alpha-1,4-linked glycosidic linkages, but can also hydrolyze alpha-1,6-linked glucans (PubMed:29061980).PTM The different forms of acid glucosidase are obtained by proteolytic processing.PTM Phosphorylation of mannose residues ensures efficient transport of the enzyme to the lysosomes via the mannose 6-phosphate receptor.POLYMORPHISM There are three common alleles of GAA: GAA*1, GAA*2 and GAA*4. The sequence shown is that of allele GAA*1, which is the most common. Alleles GAA*2 and GAA*4 are much rarer.SIMILARITY Belongs to the glycosyl hydrolase 31 family. UniProt P10253 521 EQUAL Reactome Database ID Release 78 5357598 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=5357598 Reactome R-HSA-5357598 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-5357598.1 GAA M318T lysosomal alpha-glucosidase M318T acid maltase M318T Reactome DB_ID: 5357607 318 EQUAL L-methionine removal MOD MOD:01643 Reactome Database ID Release 78 5357607 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=5357607 Reactome R-HSA-5357607 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-5357607.1 Reactome Database ID Release 78 5357599 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=5357599 Reactome R-HSA-5357599 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-5357599.1 GENE ONTOLOGY GO:0090599 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 GSD IV Glycogen storage disease type IV (GBE1) 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 LEFT-TO-RIGHT 2.4.1.18 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 polyGlc-GYG2:GYS2-a tetramer Reactome DB_ID: 3322056 1 GYS2 glycogen synthase 2 Glycogen (starch) synthase, liver Reactome DB_ID: 71599 1 EQUAL 703 EQUAL Reactome Database ID Release 78 71599 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=71599 Reactome R-HSA-71599 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-71599.1 2 poly((1,4)-alpha-glucosyl)GYG2 poly((1,4)-alpha-glucosyl) glycogenin-2 Reactome DB_ID: 70188 228 EQUAL 1 EQUAL 501 EQUAL Reactome Database ID Release 78 70188 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=70188 Reactome R-HSA-70188 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-70188.1 2 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 ACTIVATION Converted from EntitySet in Reactome GBE1 mutants Reactome DB_ID: 3878772 GBE1 F257L glycogen branching enzyme F257L 1,4-alpha-glucan branching enzyme F257L Brancher enzyme F257L Reactome DB_ID: 3878767 UniProt:Q04446 GBE1 GBE1 FUNCTION Required for normal glycogen accumulation (PubMed:8463281, PubMed:26199317, PubMed:8613547). The alpha 1-6 branches of glycogen play an important role in increasing the solubility of the molecule (Probable).PATHWAY Glycan biosynthesis; glycogen biosynthesis.SUBUNIT Monomer.DOMAIN Binds its carbohydrate substrate close to the active site, but also via regions close to the N-terminus; this may result in increased affinity and therefore increased catalytic efficiency.DISEASE Neuromuscular perinatal glycogen storage disease type 4 is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.SIMILARITY Belongs to the glycosyl hydrolase 13 family. GlgB subfamily. UniProt Q04446 257 EQUAL 1 EQUAL 702 EQUAL Reactome Database ID Release 78 3878767 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=3878767 Reactome R-HSA-3878767 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-3878767.1 GBE1 R515C glycogen branching enzyme R515C 1,4-alpha-glucan branching enzyme R515C Brancher enzyme R515C Reactome DB_ID: 3878775 515 EQUAL 1 EQUAL 702 EQUAL Reactome Database ID Release 78 3878775 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=3878775 Reactome R-HSA-3878775 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-3878775.1 Reactome Database ID Release 78 3878772 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=3878772 Reactome R-HSA-3878772 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-3878772.1 GENE ONTOLOGY GO:0003844 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 GSD XV Glycogen storage disease type XV (GYG1) 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 LEFT-TO-RIGHT 2.4.1.186 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 GYG1:GYS1-a tetramer Reactome DB_ID: 3322050 1 GYG1 glycogenin-1 GN-1 Reactome DB_ID: 70190 2 EQUAL 350 EQUAL Reactome Database ID Release 78 70190 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=70190 Reactome R-HSA-70190 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-70190.1 2 2 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 8 ACTIVATION mutant GYG1:GYS1-a tetramer Reactome DB_ID: 9037663 1 GYG1 T83M glycogenin-1 T83M GN-1 T83M Reactome DB_ID: 3814832 83 EQUAL L-threonine removal MOD MOD:01647 2 EQUAL 350 EQUAL Reactome Database ID Release 78 3814832 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=3814832 Reactome R-HSA-3814832 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-3814832.1 2 2 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 GENE ONTOLOGY GO:0008466 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 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 LEFT-TO-RIGHT 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 H2O water Reactome DB_ID: 29356 Reactome Database ID Release 78 29356 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=29356 Reactome R-ALL-29356 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-ALL-29356.5 COMPOUND C00001 laforin:PTG:phosphoglycogen-GYG1:GYS1-a tetramer EPM2A:PPP1R3C:phosphoglycogen-GYG1:GYS1-a tetramer Reactome DB_ID: 3780999 1 PTG PPP1R3C Protein phosphatase 1 regulatory subunit 3C Protein targeting to glycogen PPP1R5 Reactome DB_ID: 3777102 UniProt:Q9UQK1 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 Database ID Release 78 3777102 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=3777102 Reactome R-HSA-3777102 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-3777102.1 1 EPM2A dimer Reactome DB_ID: 6805697 EPM2A Laforin Reactome DB_ID: 3777103 UniProt:O95278 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 3777103 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=3777103 Reactome R-HSA-3777103 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-3777103.1 2 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 1 2 polysaccharide-P-GYG1 polysaccharide-P-glycogenin-1 Reactome DB_ID: 3777092 195 EQUAL 2 EQUAL 350 EQUAL Reactome Database ID Release 78 3777092 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=3777092 Reactome R-HSA-3777092 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-3777092.1 2 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 ACTIVATION mutant laforin:PTG:phosphoglycogen-GYG1:GYS1-a tetramer mutant EPM2A:PPP1R3C:phosphoglycogen-GYG1:GYS1-a tetramer Reactome DB_ID: 9037665 1 1 2 EPM2A mutant dimer Reactome DB_ID: 9037666 Converted from EntitySet in Reactome EPM2A mutants Laforin mutants Reactome DB_ID: 3791352 EPM2A F84L Laforin F84L Reactome DB_ID: 3791363 84 EQUAL 1 EQUAL 331 EQUAL Reactome Database ID Release 78 3791363 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=3791363 Reactome R-HSA-3791363 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-3791363.1 EPM2A P301L Laforin P301L Reactome DB_ID: 3791357 301 EQUAL 1 EQUAL 331 EQUAL Reactome Database ID Release 78 3791357 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=3791357 Reactome R-HSA-3791357 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-3791357.1 EPM2A T194I Laforin T194I Reactome DB_ID: 3791361 194 EQUAL 1 EQUAL 331 EQUAL Reactome Database ID Release 78 3791361 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=3791361 Reactome R-HSA-3791361 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-3791361.1 Reactome Database ID Release 78 3791352 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=3791352 Reactome R-HSA-3791352 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-3791352.1 2 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 1 2 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 GENE ONTOLOGY GO:0019203 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 LEFT-TO-RIGHT 6.3.2.19 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 laforin:PTG:glycogen-GYG1:GYS1-a tetramer EPM2A:PPP1R3C:glycogen-GYG1:GYS1-a tetramer Reactome DB_ID: 3781000 1 1 1 2 glycogen-GYG1 glycogen-glycogenin-1 Reactome DB_ID: 70174 2 EQUAL 350 EQUAL Reactome Database ID Release 78 70174 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=70174 Reactome R-HSA-70174 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-70174.1 2 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 Ub ubiquitin Reactome DB_ID: 113595 RPS27A RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939205 UniProt:P62979 RPS27A RPS27A UBA80 UBCEP1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62979 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939205 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=939205 Reactome R-HSA-939205 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-939205.1 UBA52 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939203 UniProt:P62987 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62987 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939203 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=939203 Reactome R-HSA-939203 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-939203.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939214 UniProt:P0CG47 UBB UBB SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG47 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939214 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=939214 Reactome R-HSA-939214 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-939214.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939213 77 EQUAL 152 EQUAL Reactome Database ID Release 78 939213 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=939213 Reactome R-HSA-939213 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-939213.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939230 153 EQUAL 228 EQUAL Reactome Database ID Release 78 939230 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=939230 Reactome R-HSA-939230 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-939230.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939188 UniProt:P0CG48 UBC UBC MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG48 1 EQUAL 76 EQUAL Reactome Database ID Release 78 939188 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=939188 Reactome R-HSA-939188 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-939188.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939164 77 EQUAL 152 EQUAL Reactome Database ID Release 78 939164 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=939164 Reactome R-HSA-939164 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-939164.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939258 153 EQUAL 228 EQUAL Reactome Database ID Release 78 939258 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=939258 Reactome R-HSA-939258 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-939258.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939192 229 EQUAL 304 EQUAL Reactome Database ID Release 78 939192 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=939192 Reactome R-HSA-939192 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-939192.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939232 305 EQUAL 380 EQUAL Reactome Database ID Release 78 939232 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=939232 Reactome R-HSA-939232 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-939232.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939191 381 EQUAL 456 EQUAL Reactome Database ID Release 78 939191 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=939191 Reactome R-HSA-939191 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-939191.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939184 457 EQUAL 532 EQUAL Reactome Database ID Release 78 939184 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=939184 Reactome R-HSA-939184 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-939184.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939239 533 EQUAL 608 EQUAL Reactome Database ID Release 78 939239 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=939239 Reactome R-HSA-939239 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-939239.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939165 609 EQUAL 684 EQUAL Reactome Database ID Release 78 939165 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=939165 Reactome R-HSA-939165 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-939165.1 Reactome Database ID Release 78 113595 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=113595 Reactome R-HSA-113595 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-113595.1 2 ACTIVATION Converted from EntitySet in Reactome malin mutants NHLRC1 mutants Reactome DB_ID: 3797212 malin C26S NHLRC1 C26S E3 ubiquitin-protein ligase NHLRC1 C26S EMP2B C26S Reactome DB_ID: 3797231 UniProt:Q6VVB1 NHLRC1 NHLRC1 EPM2B FUNCTION E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for proteasome-dependent degradation, thus decreasing glycogen accumulation. Polyubiquitinates EPM2A/laforin and ubiquitinates AGL and targets them for proteasome-dependent degradation. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with AGL. Interacts (via the NHL repeats) with EPM2A/laforin. Forms a complex with EPM2A/laforin and HSP70. Interacts with PRDM8 (PubMed:22961547).TISSUE SPECIFICITY Expressed in brain, cerebellum, spinal cord, medulla, heart, liver, skeletal muscle and pancreas.DOMAIN The RING domain is essential for ubiquitin E3 ligase activity. UniProt Q6VVB1 26 EQUAL 1 EQUAL 395 EQUAL Reactome Database ID Release 78 3797231 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=3797231 Reactome R-HSA-3797231 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-3797231.1 malin F33S NHLRC1 F33S E3 ubiquitin-protein ligase NHLRC1 F33S EMP2B F33S Reactome DB_ID: 3797218 33 EQUAL 1 EQUAL 395 EQUAL Reactome Database ID Release 78 3797218 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=3797218 Reactome R-HSA-3797218 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-3797218.1 Reactome Database ID Release 78 3797212 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=3797212 Reactome R-HSA-3797212 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-3797212.1 GENE ONTOLOGY GO:0004842 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 SCN4 Severe congenital neutropenia type 4 (G6PC3) 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 LEFT-TO-RIGHT 3.1.3.9 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 ACTIVATION Converted from EntitySet in Reactome G6PC3 mutants Reactome DB_ID: 3282874 G6PC3 G260R Reactome DB_ID: 3276581 UniProt:Q9BUM1 G6PC3 G6PC3 UGRP FUNCTION Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. May form with the glucose-6-phosphate transporter (SLC37A4/G6PT) a ubiquitously expressed complex responsible for glucose production through glycogenolysis and gluconeogenesis. Probably required for normal neutrophil function.ACTIVITY REGULATION Inhibited by vanadate.PATHWAY Carbohydrate biosynthesis; gluconeogenesis.TISSUE SPECIFICITY Ubiquitously expressed. Highly expressed in skeletal muscle, at intermediate levels in heart, brain, placenta, kidney, colon, thymus, spleen and pancreas. Also detected in testis, prostate, ovary, liver, lung, small intestine and peripheral blood lymphocytes.SIMILARITY Belongs to the glucose-6-phosphatase family.CAUTION According to PubMed:12370122, it has no hydrolytic activity. UniProt Q9BUM1 260 EQUAL 1 EQUAL 346 EQUAL Reactome Database ID Release 78 3276581 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=3276581 Reactome R-HSA-3276581 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-3276581.1 G6PC3 R253H Reactome DB_ID: 3276572 253 EQUAL 1 EQUAL 346 EQUAL Reactome Database ID Release 78 3276572 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=3276572 Reactome R-HSA-3276572 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-3276572.1 Reactome Database ID Release 78 3282874 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=3282874 Reactome R-HSA-3282874 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-3282874.1 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 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 LEFT-TO-RIGHT 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 Fru 1-P D-Fructose 1-phosphate keto-D-fructose 1-phosphate Reactome DB_ID: 31221 keto-D-fructose 1-phosphate [ChEBI:18105] keto-D-fructose 1-phosphate ChEBI CHEBI:18105 Reactome Database ID Release 78 31221 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=31221 Reactome R-ALL-31221 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-ALL-31221.3 COMPOUND C01094 ACTIVATION Converted from EntitySet in Reactome ALDOB mutant proteins Reactome DB_ID: 5656450 ALDOB A149P dimer Reactome DB_ID: 5656445 ALDOB A149P Fructose-bisphosphate aldolase B A149P Liver-type aldolase A149P Reactome DB_ID: 5656457 UniProt:P05062 ALDOB ALDOB ALDB PATHWAY Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 4/4.SUBUNIT Homotetramer. Interacts with BBS1, BBS2, BBS4 and BBS7.MISCELLANEOUS In vertebrates, 3 forms of this ubiquitous glycolytic enzyme are found, aldolase A in muscle, aldolase B in liver and aldolase C in brain.SIMILARITY Belongs to the class I fructose-bisphosphate aldolase family. UniProt P05062 149 EQUAL 2 EQUAL 364 EQUAL Reactome Database ID Release 78 5656457 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=5656457 Reactome R-HSA-5656457 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-5656457.1 2 Reactome Database ID Release 78 5656445 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=5656445 Reactome R-HSA-5656445 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-5656445.1 ALDOB A174D tetramer Reactome DB_ID: 5656440 ALDOB A174D Fructose-bisphosphate aldolase B A174D Liver-type aldolase A174D Reactome DB_ID: 5656456 174 EQUAL 2 EQUAL 364 EQUAL Reactome Database ID Release 78 5656456 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=5656456 Reactome R-HSA-5656456 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-5656456.1 4 Reactome Database ID Release 78 5656440 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=5656440 Reactome R-HSA-5656440 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-5656440.1 Reactome Database ID Release 78 5656450 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=5656450 Reactome R-HSA-5656450 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-5656450.1 GENE ONTOLOGY GO:0061609 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 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 LEFT-TO-RIGHT 2.7.1.3 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 Fru Levulose D-fructose Fruit sugar D-Arabino-hexulose Reactome DB_ID: 29532 D-fructose [ChEBI:15824] D-fructose ChEBI CHEBI:15824 Reactome Database ID Release 78 29532 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=29532 Reactome R-ALL-29532 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-ALL-29532.3 COMPOUND C10906 COMPOUND C00095 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 78 113592 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=113592 Reactome R-ALL-113592 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-ALL-113592.5 COMPOUND C00002 ACTIVATION Converted from EntitySet in Reactome KHK mutant dimers Reactome DB_ID: 5656460 KHK A43T dimer Reactome DB_ID: 5656448 KHK A43T Ketohexokinase A43T Hepatic fructokinase A43T Reactome DB_ID: 5656462 UniProt:P50053 KHK KHK FUNCTION Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate.ACTIVITY REGULATION Requires potassium. Inhibition by ADP.PATHWAY Carbohydrate metabolism; fructose metabolism.SUBUNIT Homodimer.TISSUE SPECIFICITY Most abundant in liver, kidney, gut, spleen and pancreas. Low levels also found in adrenal, muscle, brain and eye.SIMILARITY Belongs to the carbohydrate kinase PfkB family. UniProt P50053 43 EQUAL 1 EQUAL 298 EQUAL Reactome Database ID Release 78 5656462 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=5656462 Reactome R-HSA-5656462 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-5656462.1 2 Reactome Database ID Release 78 5656448 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=5656448 Reactome R-HSA-5656448 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-5656448.1 KHK G40R dimer Reactome DB_ID: 5656443 KHK G40R Ketohexokinase G40R Hepatic fructokinase G40R Reactome DB_ID: 5656458 40 EQUAL 1 EQUAL 298 EQUAL Reactome Database ID Release 78 5656458 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=5656458 Reactome R-HSA-5656458 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-5656458.1 2 Reactome Database ID Release 78 5656443 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=5656443 Reactome R-HSA-5656443 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-5656443.1 Reactome Database ID Release 78 5656460 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=5656460 Reactome R-HSA-5656460 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-5656460.1 GENE ONTOLOGY GO:0004454 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, 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 LEFT-TO-RIGHT 1.1.1.10 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 H+ proton hydron Reactome DB_ID: 70106 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 78 70106 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=70106 Reactome R-ALL-70106 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-ALL-70106.4 COMPOUND C00080 L-xylulose Reactome DB_ID: 5660036 L-xylulose [ChEBI:17399] L-xylulose ChEBI CHEBI:17399 Reactome Database ID Release 78 5660036 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=5660036 Reactome R-ALL-5660036 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-ALL-5660036.2 TPNH NADPH Reactome DB_ID: 29364 NADPH(4-) [ChEBI:57783] NADPH(4-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH NADPH tetraanion ChEBI CHEBI:57783 Reactome Database ID Release 78 29364 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=29364 Reactome R-ALL-29364 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-ALL-29364.3 COMPOUND C00005 ACTIVATION DCXR H195Tfs*7 L-xylulose reductase H195Tfs*7 Reactome DB_ID: 5662854 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:Q7Z4W1 DCXR DCXR SDR20C1 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 Reactome Database ID Release 78 5662854 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=5662854 Reactome R-HSA-5662854 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-5662854.1 GENE ONTOLOGY GO:0050038 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 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 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 LEFT-TO-RIGHT 5.3.1.6 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 RU5P D-ribulose 5-phosphate Reactome DB_ID: 29732 D-ribulose 5-phosphate [ChEBI:17363] D-ribulose 5-phosphate ChEBI CHEBI:17363 Reactome Database ID Release 78 29732 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=29732 Reactome R-ALL-29732 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-ALL-29732.3 COMPOUND C00199 ACTIVATION RPIA A61V ribose 5-phosphate isomerase A61V Reactome DB_ID: 5660009 UniProt:P49247 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 61 EQUAL 1 EQUAL 311 EQUAL Reactome Database ID Release 78 5660009 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=5660009 Reactome R-HSA-5660009 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-5660009.1 GENE ONTOLOGY GO:0004751 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 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 LEFT-TO-RIGHT 5.3.1.6 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 R5P aldehydo-D-ribose 5-phosphate D-ribose 5-phosphate Ribose 5-phosphate Reactome DB_ID: 73578 D-ribofuranose 5-phosphate(2-) [ChEBI:78346] D-ribofuranose 5-phosphate(2-) 5-O-phosphonato-D-ribofuranose D-ribose 5-phosphate ChEBI CHEBI:78346 Reactome Database ID Release 78 73578 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=73578 Reactome R-ALL-73578 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-ALL-73578.5 COMPOUND C00117 ACTIVATION 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 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 LEFT-TO-RIGHT 2.2.1.2 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 Fru(6)P D-Fructose 6-phosphate keto-D-fructose 6-phosphate D-Fructose 6-phosphoric acid Neuberg ester D-fructose 6-phosphate(2-) Reactome DB_ID: 29512 beta-D-fructofuranose 6-phosphate(2-) [ChEBI:57634] beta-D-fructofuranose 6-phosphate(2-) beta-D-fructofuranose 6-phosphate dianion 6-O-phosphonato-beta-D-fructofuranose ChEBI CHEBI:57634 Reactome Database ID Release 78 29512 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=29512 Reactome R-ALL-29512 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-ALL-29512.4 COMPOUND C00085 E4P D-Erythrose 4-phosphate D-erythrose 4-phosphate(2-) Reactome DB_ID: 29878 D-erythrose 4-phosphate(2-) [ChEBI:16897] D-erythrose 4-phosphate(2-) ChEBI CHEBI:16897 Reactome Database ID Release 78 29878 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=29878 Reactome R-ALL-29878 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-ALL-29878.3 COMPOUND C00279 ACTIVATION Converted from EntitySet in Reactome TALDO1 mutant dimers Reactome DB_ID: 5660002 TALDO1 R192C dimer Reactome DB_ID: 5659982 TALDO1 R192C transaldolase 1 R192C Reactome DB_ID: 5659976 UniProt:P37837 TALDO1 TALDO1