BioPAX pathway converted from "The citric acid (TCA) cycle and respiratory electron transport" in the Reactome database. The citric acid (TCA) cycle and respiratory electron transport The citric acid (TCA) cycle and respiratory electron transport This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Pyruvate metabolism and Citric Acid (TCA) cycle Pyruvate metabolism and Citric Acid (TCA) cycle This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Pyruvate metabolism Pyruvate metabolism Cori Cycle (interconversion of glucose and lactate) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 1.1.1.40 ME1:Mg2+ tetramer oxidatively decarboxylates MAL to PYR ME1:Mg2+ tetramer oxidatively decarboxylates MAL to PYR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 198498 1 cytosol GO 0005829 (S)-malate(2-) [ChEBI:15589] (S)-malate(2-) (S)-malate Reactome http://www.reactome.org ChEBI 15589 Reactome DB_ID: 29366 1 NADP(3-) [ChEBI:58349] NADP(3-) NADP(+) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP trianion ChEBI 58349 Reactome DB_ID: 29398 1 pyruvate [ChEBI:15361] pyruvate 2-oxopropanoate 2-oxopropanoic acid, ion(1-) ChEBI 15361 Reactome DB_ID: 70106 1 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 113528 1 carbon dioxide [ChEBI:16526] carbon dioxide ChEBI 16526 Reactome DB_ID: 29364 1 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion ChEBI 57783 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10517035 ME1:Mg2+ tetramer [cytosol] ME1:Mg2+ tetramer Reactome DB_ID: 10517033 2 ME1:Mg2+ dimer [cytosol] ME1:Mg2+ dimer Reactome DB_ID: 10517031 2 ME1:Mg2+ [cytosol] ME1:Mg2+ Reactome DB_ID: 29926 1 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI 18420 Reactome DB_ID: 10517029 1 UniProt:A0A6I8S9Q0 me1 Xenopus tropicalis NCBI Taxonomy 8364 UniProt A0A6I8S9Q0 Chain Coordinates 1 EQUAL 572 EQUAL Reactome Database ID Release 81 10517031 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517031 Reactome R-XTR-9012030 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-XTR-9012030.1 Reactome Database ID Release 81 10517033 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517033 Reactome R-XTR-9012024 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-XTR-9012024.1 Reactome Database ID Release 81 10517035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517035 Reactome R-XTR-9012061 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-XTR-9012061.1 GO 0004473 GO molecular function Reactome Database ID Release 81 10517036 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517036 Reactome Database ID Release 81 10517038 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517038 Reactome R-XTR-9012036 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-XTR-9012036.1 One hallmark of cancer is altered cellular metabolism. Malic enzymes (MEs) are a family of homotetrameric enzymes that catalyse the reversible oxidative decarboxylation of L-malate to pyruvate, with a simultaneous reduction of NAD(P)+ to NAD(P)H. As MEs generate NADPH and NADH, they may play roles in energy production and reductive biosynthesis. Humans possess three ME isoforms; ME1 is cytosolic and utilises NADP+, ME3 is mitochondrial and can utilise NADP+ and ME2 is mitochondrial and can utililse either NAD+ or NADP+ (Chang & Tong 2003, Murugan & Hung 2012).<br><br>NADP-dependent malic enzyme (ME1, aka c-NADP-ME) is a cytosolic enzyme that oxidatively decarboxylates (s)-malate (MAL) to pyruvate (PYR) and CO2 using NADP+ as cofactor (Zelewski & Swierczynski 1991). ME1 exists as a dimer of dimers (Murugan & Hung 2012, Hsieh et al. 2014) and a divalent metal such as Mg2+ is essential for catalysis (Chang & Tong 2003). 14596586 Pubmed 2003 Structure and function of malic enzymes, a new class of oxidative decarboxylases Chang, Gu-Gang Tong, L Biochemistry 42:12721-33 23284632 Pubmed 2012 Biophysical characterization of the dimer and tetramer interface interactions of the human cytosolic malic enzyme Murugan, Sujithkumar Hung, Hui-Chih PLoS ONE 7:e50143 24998673 Pubmed 2014 Structural characteristics of the nonallosteric human cytosolic malic enzyme Hsieh, Ju-Yi Li, Shao-Yu Chen, Meng-Chun Yang, Pai-Chun Chen, Hui-Yi Chan, Nei-Li Liu, Jyung-Hurng Hung, Hui-Chih Biochim. Biophys. Acta 1844:1773-83 1935931 Pubmed 1991 Malic enzyme in human liver. Intracellular distribution, purification and properties of cytosolic isozyme Zelewski, M Swierczyński, J Eur. J. Biochem. 201:339-45 inferred by electronic annotation IEA GO IEA 1.1.1.27 LDH tetramer reduces PYR to LACT LDH tetramer reduces PYR to LACT Pyruvate + NADH + H+ <=> (S)-Lactate + NAD+ This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29398 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 73473 1 NADH(2-) [ChEBI:57945] NADH(2-) NADH dianion adenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADH ChEBI 57945 Reactome DB_ID: 29360 1 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Reactome DB_ID: 29708 1 (S)-lactic acid [ChEBI:422] (S)-lactic acid ChEBI 422 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10429590 LDH tetramer [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004459 GO molecular function Reactome Database ID Release 81 10429591 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429591 Reactome Database ID Release 81 10430644 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430644 Reactome R-XTR-71849 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-XTR-71849.1 Cytosolic lactate dehydrogenase (LDH) catalyzes the freely reversible reaction of pyruvate (PYR) and NADH + H+ to form lactate (LACT) and NAD+. In liver parenchymal cells, this reaction allows lactate from red blood cells and exercising muscle to be converted to pyruvate which in turn is typically used for gluconeogenesis which also consumes the NADH from the reaction.<p>Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found (Read et al. 2001; Sakai et al. 1987; Yu et al. 2001). A third isoform, C, and its tetramer, C4, are found in testis (Millan et al. 1987; LeVan & Goldberg 1991). A fourth isoform, LDHAL6A, is less fully characterized than these others but limited data suggest that it may be testis-specific (Chen et al. 2009). 11377399 Pubmed 2001 Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4 Yu, Y Deck, JA Hunsaker, LA Deck, LM Royer, RE Goldberg, Erwin Vander Jagt, DL Biochem Pharmacol 62:81-9 1996957 Pubmed 1991 Properties of human testis-specific lactate dehydrogenase expressed from Escherichia coli LeVan, Kay M Goldberg, Erwin Biochem. J. 273:587-92 11276087 Pubmed 2001 Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase Read, JA Winter, VJ Eszes, CM Sessions, RB Brady, RL Proteins 43:175-85 3435492 Pubmed 1987 The cDNA and protein sequences of human lactate dehydrogenase B Sakai, I Sharief, FS Pan, YC Li, SS Biochem J 248:933-6 18351441 Pubmed 2009 Identification of a novel human lactate dehydrogenase gene LDHAL6A, which activates transcriptional activities of AP1(PMA) Chen, Xinya Gu, Xiuting Shan, Yuxi Tang, Wenwen Yuan, Jian Zhong, Zhaomin Wang, Yingli Huang, Weixue Wan, Bo Yu, Long Mol. Biol. Rep. 36:669-76 2440048 Pubmed 1987 Epitopes of human testis-specific lactate dehydrogenase deduced from a cDNA sequence Millan, Jose Luis Driscoll, Catherine E LeVan, Kay M Goldberg, Erwin Proc. Natl. Acad. Sci. U.S.A. 84:5311-5 inferred by electronic annotation IEA GO IEA 1.1.1.27 LDHAL6B reduces PYR to LACT LDHAL6B reduces PYR to LACT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113529 1 mitochondrial matrix GO 0005759 Reactome DB_ID: 113557 1 Reactome DB_ID: 29362 1 Reactome DB_ID: 6807616 1 Reactome DB_ID: 113526 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10505656 UniProt:Q6P7L5 ldha UniProt Q6P7L5 1 EQUAL 381 EQUAL Reactome Database ID Release 81 10505657 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10505657 Reactome Database ID Release 81 10505659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10505659 Reactome R-XTR-6807826 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-XTR-6807826.1 LDHAL6B (L-lactate dehydrogenase A-like 6B) catalyzes the reaction of PYR (pyruvate) and NADH + H+ to form LACT (lactate) and NAD+. The LDHAL6B protein is the inferred product of an open reading frame transcribed in the testis (Wang et al. 2005). Its mitochondrial localization is inferred from the presence of a mitochondrial localization sequence at its amino terminus (Holmes and Goldberg 2009). A physiological role for lactate formation from the abundant pyruvate and NADH expected in rapidly respiring mitochondria is not straightforward to imagine, however. 15870898 Pubmed 2005 Cloning and characterization of a novel intronless lactate dehydrogenase gene in human testis Wang, Hui Zhou, Zuomin Lu, Li Xu, Zhiyang Sha, Jiahao Int. J. Mol. Med. 15:949-53 19679512 Pubmed 2009 Computational analyses of mammalian lactate dehydrogenases: human, mouse, opossum and platypus LDHs Holmes, Roger S Goldberg, Erwin Comput Biol Chem 33:379-85 inferred by electronic annotation IEA GO IEA 1.1.1.27 LDH tetramer oxidises LACT to PYR LDH tetramer oxidises LACT to PYR (S)-Lactate + NAD+ <=> Pyruvate + NADH + H+ This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29360 1 Reactome DB_ID: 29708 1 Reactome DB_ID: 29398 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 73473 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10429590 Reactome Database ID Release 81 10429593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429593 Reactome R-XTR-70510 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-XTR-70510.1 Cytosolic lactate dehydrogenase catalyzes the freely reversible reaction of lactate and NAD+ to form pyruvate and NADH + H+. In liver parenchymal cells, this reaction allows lactate from red blood cells and exercising muscle to be converted to pyruvate which in turn is typically used for gluconeogenesis which also consumes the NADH from the reaction.<p>Lactate dehydrogenase is active as a tetramer. Two isoforms of lactate dehydrogenase, A and B, are widely expressed in human tissues, and all five tetramers - A4, A3B, A2B2, AB3, and B4 - are found (Read et al. 2001; Sakai et al. 1987; Yu et al. 2001). A third isoform, C, and its tetramer, C4, are found in testis (Millan et al. 1987; LeVan & Goldberg 1991). A fourth isoform, LDHAL6A, is less fully characterized than these others but limited data suggest that it may be testis-specific (Chen et al. 2009). inferred by electronic annotation IEA GO IEA VDAC1 transports PYR from cytosol to mitochondrial intermembrane space VDAC1 transports PYR from cytosol to mitochondrial intermembrane space This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29398 1 Reactome DB_ID: 9012375 1 mitochondrial intermembrane space GO 0005758 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10487873 mitochondrial outer membrane GO 0005741 UniProt:Q28HL9 vdac1 UniProt Q28HL9 2 EQUAL 283 EQUAL GO 0008308 GO molecular function Reactome Database ID Release 81 10517080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517080 Reactome Database ID Release 81 10517082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517082 Reactome R-XTR-9012374 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-XTR-9012374.1 Similar to other ions and metabolites, pyruvate (PYR) probably crosses the outer mitochondrial membrane through the relatively non-specific, voltage-dependent anion-selective channel protein 1 (VDAC1) (McCommis & Finck 2015). Humans with defective VDAC1 show impaired PYR oxidation and ATP production (Huizing et al. 1996). 8726225 Pubmed 1996 Deficiency of the voltage-dependent anion channel: a novel cause of mitochondriopathy Huizing, M Ruitenbeek, W Thinnes, F P DePinto, V Wendel, U Trijbels, F J Smit, L M ter Laak, H J van den Heuvel, L P Pediatr. Res. 39:760-5 25748677 Pubmed 2015 Mitochondrial pyruvate transport: a historical perspective and future research directions McCommis, Kyle S Finck, Brian N Biochem. J. 466:443-54 inferred by electronic annotation IEA GO IEA lipo-PDH decarboxylates PYR to Ac-CoA lipo-PDH decarboxylates PYR to Ac-CoA pyruvate + CoASH + NAD+ => acetylCoA + CO2 + NADH + H+ Oxidative decarboxylation of pyruvate to acetyl CoA by pyruvate dehydrogenase This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29374 1 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} ChEBI 57287 Reactome DB_ID: 113557 1 Reactome DB_ID: 113526 1 Reactome DB_ID: 29376 1 Reactome DB_ID: 113559 1 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-CoA acetyl-CoA tetraanion acetyl-coenzyme A(4-) AcCoA(4-) ChEBI 57288 Reactome DB_ID: 29362 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10430309 lipo-PDH [mitochondrial matrix] lipo-PDH Reactome DB_ID: 10430303 20 lipo-K-132,K259-DLAT trimer [mitochondrial matrix] lipo-K-132,K259-DLAT trimer Reactome DB_ID: 10430301 3 UniProt:F6Z0R6 dlat UniProt F6Z0R6 N6-lipoyl-L-lysine at 132 (in Homo sapiens) 132 EQUAL N6-lipoyl-L-lysine [MOD:00127] N6-lipoyl-L-lysine at 259 (in Homo sapiens) 259 EQUAL 87 EQUAL 647 EQUAL Reactome Database ID Release 81 10430303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430303 Reactome R-XTR-69971 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-XTR-69971.1 Reactome DB_ID: 10430307 12 UniProt:A0A6I8RWC7 pdhx UniProt A0A6I8RWC7 54 EQUAL 501 EQUAL Reactome DB_ID: 10430295 22 PDH E1 [mitochondrial matrix] PDH E1 Reactome DB_ID: 10430287 2 UniProt:Q5BKI5 pdhb UniProt Q5BKI5 31 EQUAL 359 EQUAL Reactome DB_ID: 10430291 2 UniProt:A0A803KHT8 pdha1 UniProt A0A803KHT8 31 EQUAL 390 EQUAL Reactome DB_ID: 113547 2 thiamine(1+) diphosphate(3-) [ChEBI:58937] thiamine(1+) diphosphate(3-) thiamine diphosphate thiamine diphosphate dianion thiamine diphosphate(2-) ChEBI 58937 Reactome Database ID Release 81 10430295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430295 Reactome R-XTR-69968 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-XTR-69968.1 Reactome DB_ID: 10429770 6 aKADH E3 dimer [mitochondrial matrix] aKADH E3 dimer Reactome DB_ID: 10429768 2 aKADH E3 [mitochondrial matrix] aKADH E3 Reactome DB_ID: 10429766 1 UniProt:A0A6I8R6Y1 dld UniProt A0A6I8R6Y1 36 EQUAL 509 EQUAL Reactome DB_ID: 113596 1 FAD(3-) [ChEBI:57692] FAD(3-) FAD FAD trianion ChEBI 57692 Reactome Database ID Release 81 10429768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429768 Reactome R-XTR-69979 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-XTR-69979.1 Reactome Database ID Release 81 10429770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429770 Reactome R-XTR-69980 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-XTR-69980.1 Reactome Database ID Release 81 10430309 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430309 Reactome R-XTR-70070 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-XTR-70070.1 GO 0004738 GO molecular function Reactome Database ID Release 81 10430310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430310 Reactome Database ID Release 81 10430312 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430312 Reactome R-XTR-71397 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-XTR-71397.1 The mitochondrial pyruvate dehydrogenase complex catalyzes the reaction of pyruvate, CoASH, and NAD+ to form acetylCoA, CO2, and NADH. The enzyme complex contains multiple copies of three different proteins, E1 alpha, E1 beta, E2, and E3, each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001). The reaction starts with the oxidative decarboxylation of pyruvate catalyzed by E1 alpha and beta (pyruvate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the acetyl group derived from pyruvate is transferred to coenzyme A in two steps catalyzed by E2 (dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with pyruvate dehydrogenase complex and subunits purified from bovine tissue and other non-human sources. Direct evidence for the roles of the corresponding human proteins comes from studies of patients expressing mutant forms of E1 alpha (Lissens et al. 2000), E1 beta (Brown et al. 2004), E2 (Head et al. 2005), and E3 (Brautigam et al. 2005). 10679936 Pubmed 2000 Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency Lissens, W De Meirleir, L Seneca, S Liebaers, I Brown, GK Brown, RM Ito, M Naito, E Kuroda, Y Kerr, DS Wexler, ID Patel, MS Robinson, BH Seyda, A Hum Mutat 15:209-19 15138885 Pubmed 2004 Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency Brown, RM Head, RA Boubriak, II Leonard, JV Thomas, NH Brown, GK Hum Genet 115:123-7 11752427 Pubmed 2001 The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Zhou, ZH McCarthy, DB O'Connor, CM Reed, LJ Stoops, JK Proc Natl Acad Sci U S A 98:14802-7 16049940 Pubmed 2005 Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency Head, RA Brown, RM Zolkipli, Z Shahdadpuri, R King, MD Clayton, Peter T Brown, GK Ann Neurol 58:234-41 2188967 Pubmed 1990 Structure-function relationships in dihydrolipoamide acyltransferases. Reed, LJ Hackert, ML J Biol Chem 265:8971-4 15946682 Pubmed 2005 Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations Brautigam, CA Chuang, JL Tomchick, DR Machius, M Chuang, DT J Mol Biol 350:543-52 inferred by electronic annotation IEA GO IEA Regulation of pyruvate dehydrogenase (PDH) complex Regulation of pyruvate dehydrogenase (PDH) complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 3.8.1 GSTZ1 dimer dehalogenates DCA to glyoxylate GSTZ1 dimer dehalogenates DCA to glyoxylate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113521 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 9010792 1 dichloroacetate [Guide to Pharmacology:4518] dichloroacetate dichloroacetic acid Guide to Pharmacology 4518 Reactome DB_ID: 904849 1 glyoxylic acid [ChEBI:16891] glyoxylic acid ChEBI 16891 Reactome DB_ID: 3301973 2 hydrogen chloride [ChEBI:17883] hydrogen chloride ChEBI 17883 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10516940 GSTZ1 dimer [mitochondrial matrix] GSTZ1 dimer Reactome DB_ID: 10516938 2 UniProt:A0A803J8A8 gstz1 UniProt A0A803J8A8 1 EQUAL 216 EQUAL Reactome DB_ID: 1655887 2 glutathione [ChEBI:16856] glutathione ChEBI 16856 Reactome Database ID Release 81 10516940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10516940 Reactome R-XTR-9011584 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-XTR-9011584.1 GO 0019120 GO molecular function Reactome Database ID Release 81 10516941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10516941 Reactome Database ID Release 81 10516943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10516943 Reactome R-XTR-9011595 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-XTR-9011595.1 In the liver, dimeric glutathione S-transferase zeta 1 (GSTZ1 dimer, aka maleylacetoacetate isomerase, MAAI) mediates the dechlorination of the drug dichloroacetate (DCA) to glyoxylate (Ammini & Stacpoole 2003, Stacpoole et al. 1998, 2008). GSTZ1 is primarily found both in the cytosol and mitochondria (Li et al. 2011). Glyoxylate, the primary metabolite of DCA metabolism, is ultimately converted to oxalate and glycine. The reaction requires (but does not consume) glutathione (GSH). GSTZ1 also catalyses the penultimate step in tyrosine catabolism, thus avoiding the accumulation of toxic tyrosine intermediates. DCA inhibits its own metabolism apparently by a post-translationally mediated inhibition of hepatic GSTZ1 (Stacpoole et al. 1998). GSTZ1 inhibition can cause the build-up of tyrosine intermediates which are able to form protein adducts. Chronic administration of DCA in adult rodents, dogs and some humans causes reversible peripheral neuropathy and hepatotoxicity, possibly because of these reactive tyrosine intermediates (Stacpoole et al. 1998, James et al. 2017). The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular chloride concentration (Shroads et al. 2008, 2012, 2015, Jahn et al. 2016, James et al. 2017). 18647626 Pubmed 2008 Role of dichloroacetate in the treatment of genetic mitochondrial diseases Stacpoole, Peter W Kurtz, Tracie L Han, Zongchao Langaee, Taimour Adv. Drug Deliv. Rev. 60:1478-87 25079374 Pubmed 2015 Haplotype variations in glutathione transferase zeta 1 influence the kinetics and dynamics of chronic dichloroacetate in children Shroads, A L Coats, B S McDonough, C W Langaee, T Stacpoole, P W J Clin Pharmacol 55:50-5 27771434 Pubmed 2017 Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1 James, MO Jahn, Stephan C Zhong, Guo Smeltz, Marci G Hu, Zhiwei Stacpoole, Peter W Pharmacol. Ther. 170:166-180 20884751 Pubmed 2011 Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1 Li, Wenjun James, MO McKenzie, Sarah C Calcutt, Nigel A Liu, Chen Stacpoole, Peter W J. Pharmacol. Exp. Ther. 336:87-94 21642471 Pubmed 2012 Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate Shroads, Albert L Langaee, Taimour Coats, Bonnie S Kurtz, Tracie L Bullock, John R Weithorn, David Gong, Yan Wagner, David A Ostrov, David A Johnson, Julie A Stacpoole, Peter W J Clin Pharmacol 52:837-49 9783540418429 ISBN 2003 Biotransformation, Toxicology and Pharmacogenomics of Dichloroacetate Stacpoole, Peter W Ammini, Chandramohan Natural Production of Organohalogen Compounds (Book): 215-234 18096758 Pubmed 2008 Age-dependent kinetics and metabolism of dichloroacetate: possible relevance to toxicity Shroads, Albert L Guo, Xu Dixit, Vaishali Liu, Hui-Ping James, MO Stacpoole, Peter W J. Pharmacol. Exp. Ther. 324:1163-71 9710704 Pubmed 1998 Pharmacokinetics, metabolism and toxicology of dichloroacetate Stacpoole, P W Henderson, G N Yan, Z Cornett, R James, M O Drug Metab. Rev. 30:499-539 26850694 Pubmed 2016 GSTZ1 expression and chloride concentrations modulate sensitivity of cancer cells to dichloroacetate Jahn, Stephan C Solayman, Mohamed Hassan M Lorenzo, Ryan J Langaee, Taimour Stacpoole, Peter W James, MO Biochim. Biophys. Acta 1860:1202-10 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 81 9034405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9034405 Reactome R-HSA-9034405 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-9034405.1 Reactome DB_ID: 1655887 INHIBITION Reactome Database ID Release 81 9011727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9011727 Reactome R-HSA-9011727 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-9011727.1 Reactome DB_ID: 9010792 2.7.11.2 PDK isoforms phosphorylate lipo-PDH PDK isoforms phosphorylate lipo-PDH PDK-catalyzed phosphorylation (inactivation) of PDC E1 alpha subunit Inactivation of PDC by phosphorylation of PDC E1 alpha component This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10430309 1 Reactome DB_ID: 113593 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 113581 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 10445553 1 p-lipo-PDH [mitochondrial matrix] p-lipo-PDH Reactome DB_ID: 10430303 20 Reactome DB_ID: 10445551 1 phosphorylated pyruvate dehydrogenase E1 complex [mitochondrial matrix] phosphorylated pyruvate dehydrogenase E1 complex Reactome DB_ID: 113547 2 Reactome DB_ID: 10430295 1 Reactome Database ID Release 81 10445551 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445551 Reactome R-XTR-204168 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-XTR-204168.1 Reactome DB_ID: 10430307 12 54 EQUAL 501 EQUAL Reactome DB_ID: 10430295 21 Reactome DB_ID: 10429770 6 Reactome Database ID Release 81 10445553 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445553 Reactome R-XTR-210342 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-XTR-210342.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10445567 PDK isoforms [mitochondrial matrix] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity pdk4 [mitochondrial matrix] pdk1 [mitochondrial matrix] pdk3 [mitochondrial matrix] UniProt Q6DFQ9 UniProt F6QN91 UniProt A9ULF7 GO 0004740 GO molecular function Reactome Database ID Release 81 10445568 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445568 Reactome Database ID Release 81 10445570 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445570 Reactome R-XTR-203946 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-XTR-203946.1 The mitochondrial pyruvate dehydrogenase (PDH) complex (lipo-PDH) irreversibly decarboxylates pyruvate to acetyl CoA, thereby serving to oxidatively remove lactate, which is in equilibrium with pyruvate, and to link glycolysis in the cytosol to the tricarboxylic acid cycle in the mitochondria matrix. Pyruvate Dehydrogenase Kinase (PDK) in the mitochondrial matrix catalyzes the phosphorylation of serine residues of the E1 alpha subunit of the PDH complex, inactivating it. Pyruvate negatively regulates this reaction, and NADH and acetyl CoA positively regulate it (Bao et al. 2004). Four PDK isoforms have been identified and shown to catalyze the phosphorylation of E1 alpha in vitro (Gudi et al. 1995, Kolobova et al. 2001, Rowles et al. 1996). They differ in their expression patterns and quantitative responses to regulatory small molecules. All four isoforms catalyze the phosphorylation of serine residues 293 ("site 1") and 300 ("site 2"); PDK1 can also catalyse the phosphorylation of serine 232 ("site 3"). Phosphorylation of a single site in a single E1 alpha subunit is sufficient for enzyme inactivation (Bowker-Kinley et al. 1998, Gudi et al. 1995, Kolobova et al. 2001, Korotchkina and Patel, 2001). The PDH-PDK axis is emerging as an important therapeutic point in genetic mitochondrial diseases, pulmonary arterial hypertension and cancer where cellular metabolism is perturbed (James et al. 2017). Dichloroacetate (DCA) is an acid salt analogue of acetic acid that is used as a drug to inhibit PDK (Li et al. 2009). The effect is to keep the PDH complex in an active form thus stimulating mitochondrial oxidative metabolism. Chronic DCA administration may cause reversible peripheral neuropathy in adults (Kaufmann et al. 2006), but is well tolerated in children and adolescents suffering from the primary mitochondrial disease lactic acidosis (Abdelmalak et al. 2013, Stacpoole et al. 2008). The Warburg effect is the observation that cancer cells prefer aerobic glycolysis to oxidative phosphorylation (Warburg 1956). Whether this effect is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. It stands true for most types of cancer cells and has become one of the hallmarks of cancer. Aerobic glycolysis produces ATP at a much faster rate than oxidative phosphorylation, confering growth advantages to tumor cells. DCA, binding to and inhibiting PDK isoforms, promotes a shift from glycolysis to oxidative phosphorylation and reversing the Warburg effect. Its potential role, alone or in combination, in several cancers is being investigated (Kankotia & Stacpoole 2014, Tran et al. 2016). 8798399 Pubmed 1996 Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human Rowles, J Scherer, SW Xi, T Majer, M Nickle, DC Rommens, JM Popov, KM Harris, RA Riebow, NL Xia, J Tsui, LC Bogardus, C Prochazka, M J Biol Chem 271:22376-82 11485553 Pubmed 2001 Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites Kolobova, E Tuganova, A Boulatnikov, I Popov, KM Biochem J 358:69-77 9405293 Pubmed 1998 Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex Bowker-Kinley, MM Davis, WI Wu, P Harris, RA Popov, KM Biochem J 329:191-6 11486000 Pubmed 2001 Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase Korotchkina, LG Patel, MS J Biol Chem 276:37223-9 7499431 Pubmed 1995 Diversity of the pyruvate dehydrogenase kinase gene family in humans Gudi, R Bowker-Kinley, MM Kedishvili, NY Zhao, Y Popov, KM J Biol Chem 270:28989-94 15491150 Pubmed 2004 Pyruvate dehydrogenase kinase isoform 2 activity limited and further inhibited by slowing down the rate of dissociation of ADP Bao, H Kasten, SA Yan, X Roche, TE Biochemistry 43:13432-41 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 81 210344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210344 Reactome R-HSA-210344 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-210344.4 Reactome DB_ID: 113557 ACTIVATION Reactome Database ID Release 81 71425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71425 Reactome R-HSA-71425 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-71425.1 Reactome DB_ID: 113559 ACTIVATION Reactome Database ID Release 81 10444230 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10444230 Reactome DB_ID: 10444227 nucleoplasm GO 0005654 RXRA:PPARD:atRA [nucleoplasm] RXRA:PPARD:atRA Reactome DB_ID: 5334804 1 all-trans-retinoic acid [ChEBI:15367] all-trans-retinoic acid ChEBI 15367 Reactome DB_ID: 10444225 1 RXRA:PPARD [nucleoplasm] RXRA:PPARD Reactome DB_ID: 10442224 1 UniProt:A0A803K2Y7 rxra UniProt A0A803K2Y7 1 EQUAL 462 EQUAL Reactome DB_ID: 10444223 1 UniProt:A0A6I8SH51 ppard UniProt A0A6I8SH51 1 EQUAL 441 EQUAL Reactome Database ID Release 81 10444225 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10444225 Reactome R-XTR-5422941 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-XTR-5422941.1 Reactome Database ID Release 81 10444227 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10444227 Reactome R-XTR-5634107 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-XTR-5634107.1 ACTIVATION Reactome Database ID Release 81 210348 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210348 Reactome R-HSA-210348 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-210348.4 Reactome DB_ID: 29362 3.1.3.43 PDP dephosphorylates p-lipo-PDH PDP dephosphorylates p-lipo-PDH PDP-catalyzed dephosphorylation (activation) of phospho E1 alpha subunit Activation of PDC by dephosphorylation of phospho-E1 alpha component This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113521 2 Reactome DB_ID: 10445553 1 Reactome DB_ID: 113548 2 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 10430309 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10445797 PDP [mitochondrial matrix] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004741 GO molecular function Reactome Database ID Release 81 10445798 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445798 Reactome Database ID Release 81 10445800 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445800 Reactome R-XTR-204169 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-XTR-204169.1 Pyruvate dehydrogenase phosphatase (PDP) in the mitochondrial matrix catalyzes the hydrolytic removal of phosphate groups from phosphoserine residues in the E1 alpha subunit of the pyruvate dehydrogenase complex. The active form of PDP is a heterodimer of a catalytic subunit and a regulatory one. Two isoforms of the catalytic subunit have been identified and biochemically characterized (Huang et al. 1998) and mutations in PDP1 have been associated with PDP deficiency in vivo (Maj et al. 2005). The properties of the human regulatory subunit have been deduced from those of its bovine homologue (Lawson et al. 1997). The activity of PDP1 is greatly enhanced through Ca2+ -dependent binding of the catalytic subunit (PDP1c) to the L2 (inner lipoyl) domain of dihydrolipoyl acetyltransferase (E2), which is also integrated in the pyruvate dehydrogenase complex. PDP activity requires Mg2+ (Huang et al. 1998). 9395502 Pubmed 1997 Cloning, expression, and properties of the regulatory subunit of bovine pyruvate dehydrogenase phosphatase Lawson, JE Park, SH Mattison, AR Yan, J Reed, LJ J Biol Chem 272:31625-9 15855260 Pubmed 2005 Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation Maj, MC MacKay, N Levandovskiy, V Addis, J Baumgartner, ER Baumgartner, MR Robinson, BH Cameron, JM J Clin Endocrinol Metab 90:4101-7 17532339 Pubmed 2007 Crystal structure of pyruvate dehydrogenase phosphatase 1 and its functional implications Vassylyev, DG Symersky, J J Mol Biol 370:417-26 9651365 Pubmed 1998 Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation Huang, B Gudi, R Wu, P Harris, RA Hamilton, J Popov, KM J Biol Chem 273:17680-8 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 81 210326 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210326 Reactome R-HSA-210326 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-210326.2 Reactome DB_ID: 109496 Reactome Database ID Release 81 10523556 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10523556 Reactome R-XTR-204174 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-XTR-204174.1 GO 0010510 GO biological process The mitochondrial pyruvate dehydrogenase (PDH) complex catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. PDH inactivation is crucial for glucose conservation when glucose is scarce, while adequate PDH activity is required to allow both ATP and fatty acid production from glucose. The mechanisms that control human PDH activity include its phosphorylation (inactivation) by pyruvate dehydrogenase kinases (PDK 1-4) and its dephosphorylation (activation, reactivation) by pyruvate dehydrogenase phosphate phosphatases (PDP 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states (Sugden and Holness 2003). 12676647 Pubmed 2003 Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs Sugden, MC Holness, MJ Am J Physiol Endocrinol Metab 284:E855-62 inferred by electronic annotation IEA GO IEA 3.1.2.6 HAGH hydrolyses (R)-S-LGSH to GSH and LACT HAGH hydrolyses (R)-S-LGSH to GSH and LACT This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 5694130 1 (R)-S-lactoylglutathione [ChEBI:15694] (R)-S-lactoylglutathione ChEBI 15694 Reactome DB_ID: 29708 1 Reactome DB_ID: 29450 1 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate anion glutathionate ion glutathione glutathionate ChEBI 57925 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10499631 HAGH-2:2xZn2+ [cytosol] HAGH-2:2xZn2+ Reactome DB_ID: 29426 2 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome DB_ID: 10499629 1 UniProt:G1K3C6 hagh UniProt G1K3C6 14 EQUAL 308 EQUAL Reactome Database ID Release 81 10499631 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10499631 Reactome R-XTR-6783206 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-XTR-6783206.1 GO 0004416 GO molecular function Reactome Database ID Release 81 10499632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10499632 Reactome Database ID Release 81 10499634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10499634 Reactome R-XTR-6783221 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-XTR-6783221.1 In the second step of the glyoxalase system, hydroxyacylglutathione hydrolase (HAGH) catalyses the hydrolysis of (R)-S-lactoylglutathione ((R)-S-LGSH) to glutathione (GSH) and lactic acid (LACT) (Ridderstrom et al. 1996). The HAGH gene can produce two forms of the protein, form 1 is mitochondrial whereas form 2 is cytosolic (Cordell et al. 2004). HAGH is monomeric but requires two Zn2+ ions for activity (Cameron et al. 1999). This reaction completes the detoxification of methylglyoxal, a reactive byproduct of pyruvate metabolism. 8550579 Pubmed 1996 Molecular cloning, heterologous expression, and characterization of human glyoxalase II Ridderström, M Saccucci, F Hellman, U Bergman, T Principato, G Mannervik, B J. Biol. Chem. 271:319-23 15117945 Pubmed 2004 The Human hydroxyacylglutathione hydrolase (HAGH) gene encodes both cytosolic and mitochondrial forms of glyoxalase II Cordell, Paul A Futers, T Simon Grant, PJ Pease, Richard J J. Biol. Chem. 279:28653-61 10508780 Pubmed 1999 Crystal structure of human glyoxalase II and its complex with a glutathione thiolester substrate analogue Cameron, A D Ridderström, M Olin, B Mannervik, B Structure 7:1067-78 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10522386 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10522386 Reactome R-XTR-70268 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-XTR-70268.1 GO 0006090 GO biological process Pyruvate sits at an intersection of key pathways of energy metabolism. It is the end product of glycolysis and the starting point for gluconeogenesis, and can be generated by transamination of alanine. It can be converted by the pyruvate dehydrogenase complex to acetyl CoA (Reed and Hackert 1990) which can enter the TCA cycle or serve as the starting point for the syntheses of long chain fatty acids, steroids, and ketone bodies depending on the tissue and metabolic state in which it is formed. It also plays a central role in balancing the energy needs of various tissues in the body. Under conditions in which oxygen supply is limiting, e.g., in exercising muscle, or in the absence of mitochondria, e.g., in red blood cells, re-oxidation of NADH produced by glycolysis cannot be coupled to generation of ATP. Instead, re-oxidation is coupled to the reduction of pyruvate to lactate. This lactate is released into the blood, and is taken up primarily by the liver, where it is oxidized to pyruvate and can be used for gluconeogenesis (Cori 1981). 7273846 Pubmed 1981 The glucose-lactic acid cycle and gluconeogenesis Cori, Carl F Curr Top Cell Regul 18:377-87 inferred by electronic annotation IEA GO IEA Citric acid cycle (TCA cycle) Citric acid cycle (TCA cycle) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2.3.3.1 Acetyl-CoA + H2O + Oxaloacetate => Citrate + CoA Acetyl-CoA + H2O + Oxaloacetate => Citrate + CoA This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113521 1 Reactome DB_ID: 113587 1 oxaloacetate(2-) [ChEBI:16452] oxaloacetate(2-) oxaloacetate dianion oxobutanedioic acid, ion(2-) oxaloacetate oxosuccinate oxobutanedioate ChEBI 16452 Reactome DB_ID: 113559 1 Reactome DB_ID: 29374 1 Reactome DB_ID: 29654 1 citric acid [ChEBI:30769] citric acid ChEBI 30769 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429950 CS dimer [mitochondrial matrix] CS dimer Reactome DB_ID: 10429948 2 UniProt:Q28DK1 cs UniProt Q28DK1 28 EQUAL 466 EQUAL Reactome Database ID Release 81 10429950 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429950 Reactome R-XTR-70973 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-XTR-70973.1 GO 0004108 GO molecular function Reactome Database ID Release 81 10429951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429951 Reactome Database ID Release 81 10429953 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429953 Reactome R-XTR-70975 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-XTR-70975.1 Mitochondrial citrate synthase dimer catalyzes the irreversible reaction of acetyl-CoA, water, and oxaloacetate to form citrate and coenzyme A. This reaction is the entry point of two-carbon units into the citric acid cycle. The reaction is subject to allosteric regulation. The gene encoding the human enzyme has been cloned (Goldenthal et al. 1998), but the enzyme has not been characterized in detail - its properties are inferred from those of the well-studied homologous pig enzyme (e.g., Morgunov and Srere 1998). 9809442 Pubmed 1998 Cloning and molecular analysis of the human citrate synthase gene Goldenthal, MJ Marin-Garcia, J Ananthakrishnan, R Genome 41:733-738 9792662 Pubmed 1998 Interaction between citrate synthase and malate dehydrogenase. Substrate channeling of oxaloacetate Morgunov, I Srere, PA J Biol Chem 273:29540-29544 inferred by electronic annotation IEA GO IEA 4.2.1.3 citrate <=> isocitrate citrate <=> isocitrate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29654 1 Reactome DB_ID: 29938 1 D-threo-isocitrate(3-) [ChEBI:15562] D-threo-isocitrate(3-) D-threo-isocitrate threo-Ds-isocitrate ChEBI 15562 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429941 UniProt:Q5I0B1 aco2 UniProt Q5I0B1 28 EQUAL 780 EQUAL GO 0003994 GO molecular function Reactome Database ID Release 81 10429942 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429942 Reactome Database ID Release 81 10429944 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429944 Reactome R-XTR-70971 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-XTR-70971.1 Mitochondrial aconitase reversibly converts citrate to isocitrate via a cis-aconitate intermediate. Mitochondrial aconitase activity has been demonstrated in diverse human tissue extracts (Slaughter et al. 1975) and a protein homologous to the well-characterized porcine enzyme has been purified from human tissues (Baldwin et al. 1991). 1052766 Pubmed 1975 Aconitase polymorphism in man Slaughter, CA Hopkinson, DA Harris, H Ann Hum Genet 39:193-202 1946331 Pubmed 1991 Purification and partial amino acid sequence of human aconitase Baldwin, GS Seet, KL Callaghan, J Toncich, G Toh, BH Moritz, RL Rubira, MR Simpson, R Protein Seq Data Anal 4:63-67 inferred by electronic annotation IEA GO IEA 4.2.1.3 isocitrate <=> citrate isocitrate <=> citrate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29938 1 Reactome DB_ID: 29654 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429941 28 EQUAL 780 EQUAL Reactome Database ID Release 81 10458080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458080 Reactome R-XTR-450975 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-XTR-450975.1 Mitochondrial aconitase reversibly converts isocitrate to citrate via a cis-aconitate intermediate. Mitochondrial aconitase activity has been demonstrated in diverse human tissue extracts (Slaughter et al. 1975) and a protein homologous to the well-characterized porcine enzyme has been purified from human tissues (Baldwin et al. 1991). inferred by electronic annotation IEA GO IEA 1.1.1.41 isocitrate + NAD+ => alpha-ketoglutarate + CO2 + NADH + H+ [IDH3] isocitrate + NAD+ => alpha-ketoglutarate + CO2 + NADH + H+ [IDH3] This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29938 1 Reactome DB_ID: 113526 1 Reactome DB_ID: 29376 1 Reactome DB_ID: 113594 1 2-oxoglutarate(2-) [ChEBI:16810] 2-oxoglutarate(2-) 2-ketoglutarate alpha-ketoglutarate 2-oxopentanedioic acid, ion(2-) 2-oxoglutarate ChEBI 16810 Reactome DB_ID: 113529 1 Reactome DB_ID: 29362 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429934 IDH3 complex [mitochondrial matrix] IDH3 complex Reactome DB_ID: 10429924 2 UniProt:F6SJ48 idh3a UniProt F6SJ48 28 EQUAL 366 EQUAL Reactome DB_ID: 10429928 1 UniProt:A0A6I8RCI5 idh3b UniProt A0A6I8RCI5 35 EQUAL 385 EQUAL Reactome DB_ID: 10429932 1 UniProt:Q5BKK0 idh3g UniProt Q5BKK0 40 EQUAL 393 EQUAL Reactome DB_ID: 113527 2 manganese(2+) [ChEBI:29035] manganese(2+) manganese(II) manganous ion MANGANESE (II) ION manganese, ion (Mn2+) Mn(2+) ChEBI 29035 Reactome Database ID Release 81 10429934 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429934 Reactome R-XTR-70965 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-XTR-70965.1 GO 0004449 GO molecular function Reactome Database ID Release 81 10429935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429935 Reactome Database ID Release 81 10429937 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429937 Reactome R-XTR-70967 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-XTR-70967.1 Mitochondrial isocitrate dehydrogenase IDH3 catalyzes the irreversible reaction of isocitrate and NAD+ to form alpha ketoglutarate, CO2, and NADH + H+. The enzyme is a heteromer containing four polypeptide chains, two IDH3A, one IDH3B, and one IDH3G, and two Mn++ (Dange and Colman 2010). It is activated by ADP (Soundar et al. 2003, 2006; Bzymek and Colman 2007). This is the first of four oxidation reactions in the citric acid cycle, and the first decarboxylation. 16737955 Pubmed 2006 Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase Soundar, S O'Hagan, M Fomulu, KS Colman, RF J Biol Chem 281:21073-81 14555658 Pubmed 2003 Evaluation by mutagenesis of the importance of 3 arginines in alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase Soundar, S Park, JH Colman, RF J Biol Chem 278:52146-52153 17432878 Pubmed 2007 Role of alpha-Asp181, beta-Asp192, and gamma-Asp190 in the distinctive subunits of human NAD-specific isocitrate dehydrogenase Bzymek, KP Colman, RF Biochemistry 46:5391-7 20435888 Pubmed 2010 Each conserved active site tyr in the three subunits of human isocitrate dehydrogenase has a different function Dange, M Colman, RF J Biol Chem 285:20520-5 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 81 451016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=451016 Reactome R-HSA-451016 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-451016.1 Reactome DB_ID: 113581 1.1.1.42 isocitrate + NADP+ => alpha-ketoglutarate + CO2 + NADPH + H+ [IDH2] isocitrate + NADP+ => alpha-ketoglutarate + CO2 + NADPH + H+ [IDH2] This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 29938 1 Reactome DB_ID: 113563 1 NADP(+) [ChEBI:18009] NADP(+) ChEBI 18009 Reactome DB_ID: 29376 1 Reactome DB_ID: 113594 1 Reactome DB_ID: 113529 1 Reactome DB_ID: 113600 1 NADPH [ChEBI:16474] NADPH TPNH ChEBI 16474 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10458086 IDH2 dimer [mitochondrial matrix] IDH2 dimer Reactome DB_ID: 10458084 2 UniProt:Q6GLF0 idh2 UniProt Q6GLF0 40 EQUAL 452 EQUAL Reactome DB_ID: 113527 2 Reactome Database ID Release 81 10458086 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458086 Reactome R-XTR-450982 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-XTR-450982.1 GO 0004450 GO molecular function Reactome Database ID Release 81 10458087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458087 Reactome Database ID Release 81 10458089 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458089 Reactome R-XTR-450984 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-XTR-450984.1 Mitochondrial isocitrate dehydrogenase IDH2 catalyzes the irreversible reaction of isocitrate and NADP+ to form alpha ketoglutarate, CO2, and NADPH + H+ (Hartong et al. 2008). The structure of the active human enzyme has not been determined experimentally, but is inferred to be a homodimer with one Mn++ bound to each subunit based on detailed studies of the homologous pig enzyme (Ceccarelli et al. 2002). NADP-specific IDH2 was the first isocitrate dehydrogenase isoenzyme to be characterized in biochemical studies of the mammalian TCA cycle (Ochoa 1948). Later work with yeast revealed the existence of both NADP-specific (IDH2-homologous) and NAD-specific (IDH3-homologous) enzymes and demonstrated the ADP-dependence of the latter (Kornberg and Pricer 1951), consistent with the now widely accepted view that IDH3 mediates the conversion of isocitrate to alpha-ketoglutarate in the TCA cycle. The physiological function of IDH2 is thus unclear. The recent observation that individuals homozygous for IDH3 mutations that sharply reduce its activity do not show symptoms of deficient energy metabolism in most tissues raises the possibility that the IDH2 reaction may play an accessory role in the TCA cycle (Hartong et al. 2008). 18914071 Pubmed 1948 Biosynthesis of tricarboxylic acids by carbon dioxide fixation; enzymatic mechanisms Ochoa, S J Biol Chem 174:133-57 14832224 Pubmed 1951 Di- and triphosphopyridine nucleotide isocitric dehydrogenases in yeast Kornberg, A Pricer, WE Jr J Biol Chem 189:123-36 18806796 Pubmed 2008 Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle Hartong, DT Dange, M McGee, TL Berson, EL Dryja, TP Colman, RF Nat Genet 40:1230-4 12207025 Pubmed 2002 Crystal structure of porcine mitochondrial NADP+-dependent isocitrate dehydrogenase complexed with Mn2+ and isocitrate. Insights into the enzyme mechanism Ceccarelli, C Grodsky, NB Ariyaratne, N Colman, RF Bahnson, BJ J Biol Chem 277:43454-62 inferred by electronic annotation IEA GO IEA 1.6.1.1 NADPH + NAD+ + H+ [cytosol] => NADP+ + NADH + H+ [mitochondrial matrix] NADPH + NAD+ + H+ [cytosol] => NADP+ + NADH + H+ [mitochondrial matrix] This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 70106 1 Reactome DB_ID: 113600 1 Reactome DB_ID: 113526 1 Reactome DB_ID: 113529 1 Reactome DB_ID: 29362 1 Reactome DB_ID: 113563 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10458075 mitochondrial inner membrane GO 0005743 NNT dimer [mitochondrial inner membrane] NNT dimer Reactome DB_ID: 10458073 2 UniProt:B2GUE7 nnt UniProt B2GUE7 44 EQUAL 1086 EQUAL Reactome Database ID Release 81 10458075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458075 Reactome R-XTR-451008 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-XTR-451008.1 GO 0008746 GO molecular function Reactome Database ID Release 81 10458076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458076 Reactome Database ID Release 81 10458078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458078 Reactome R-XTR-450971 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-XTR-450971.1 NNT (nicotinamide nucleotide transhydrogenase) associated with the inner mitochondrial membrane catalyzes the reaction of mitochondrial NADPH and NAD+ to form NADP+ and NADH. The reaction is coupled to the translocation of a proton across the inner mitochondrial membrane into the mitochondrial matrix (White et al, 2000). The active form of NNT is inferred to be a homodimer based on the known structure of its bovine homolog (Yamaguchi and Hatefi 1991). 10673423 Pubmed 2000 The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria White, SA Peake, SJ McSweeney, S Leonard, G Cotton, NP Jackson, JB Structure 8:1-12 2005110 Pubmed 1991 Mitochondrial energy-linked nicotinamide nucleotide transhydrogenase. Membrane topography of the bovine enzyme Yamaguchi, M Hatefi, Y J Biol Chem 266:5728-35 inferred by electronic annotation IEA GO IEA 1.2.1.105 alpha-ketoglutarate + CoASH + NAD+ => succinyl-CoA + CO2 + NADH + H+ alpha-ketoglutarate + CoASH + NAD+ => succinyl-CoA + CO2 + NADH + H+ Oxidative decarboxylation of alpha-ketoglutarate to succinyl CoA by alpha-ketoglutarate dehydrogenase This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113594 1 Reactome DB_ID: 29374 1 Reactome DB_ID: 113526 1 Reactome DB_ID: 29376 1 Reactome DB_ID: 29362 1 Reactome DB_ID: 70958 1 succinyl-CoA(5-) [ChEBI:57292] succinyl-CoA(5-) succinyl-coenzyme A(5-) S-(3-carboxy-propionyl)-CoA(5-) succinyl-CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-4-{[3-({2-[(3-carboxylatopropanoyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}-3-hydroxy-2,2-dimethyl-4-oxobutyl]diphosphate} S-(hydrogen succinyl)CoA(5-) succinyl-CoA pentaanion ChEBI 57292 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10430070 lipo-aKGDH [mitochondrial matrix] lipo-aKGDH Reactome DB_ID: 10430068 24 lipo-aKGDH E2 [mitochondrial matrix] lipo-aKGDH E2 Reactome DB_ID: 29824 1 lipoamide [ChEBI:17460] lipoamide ChEBI 17460 Reactome DB_ID: 10430066 1 UniProt:A0A803KLQ9 dlst UniProt A0A803KLQ9 N6-lipoyl-L-lysine at 110 (in Homo sapiens) 110 EQUAL 68 EQUAL 453 EQUAL Reactome Database ID Release 81 10430068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430068 Reactome R-XTR-69995 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-XTR-69995.1 Reactome DB_ID: 10430061 12 aKGDH E1 dimer [mitochondrial matrix] aKGDH E1 dimer Reactome DB_ID: 10430059 2 alpha-ketoglutarate dehydrogenase E1 holoenzyme [mitochondrial matrix] alpha-ketoglutarate dehydrogenase E1 holoenzyme Reactome DB_ID: 10430057 1 UniProt:A0A6I8QA02 ogdh UniProt A0A6I8QA02 41 EQUAL 1023 EQUAL Reactome DB_ID: 113547 1 Reactome Database ID Release 81 10430059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430059 Reactome R-XTR-69982 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-XTR-69982.1 Reactome Database ID Release 81 10430061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430061 Reactome R-XTR-69992 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-XTR-69992.1 Reactome DB_ID: 10429770 6 Reactome Database ID Release 81 10430070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430070 Reactome R-XTR-69996 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-XTR-69996.1 GO 0034602 GO molecular function Reactome Database ID Release 81 10430071 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430071 Reactome Database ID Release 81 10430314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430314 Reactome R-XTR-71401 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-XTR-71401.1 The mitochondrial alpha-ketoglutarate dehydrogenase complex catalyzes the reaction of alpha-ketoglutarate, CoASH, and NAD+ to form succinyl-CoA, CO2, and NADH. The enzyme complex contains multiple copies of three different proteins, E1 (OGDH), E2 (DLST), and E3 (DLD), each with distinct catalytic activities (Reed and Hackert 1990; Zhou et al 2001). The reaction starts with the oxidative decarboxylation of alpha ketoglutarate catalyzed by E1alpha and beta (alpha ketoglutarate dehydrogenase). Lipoamide cofactor associated with E1 is reduced at the same time. Next, the succinyl group derived from alpha ketoglutarate is transferred to coenzyme A in two steps catalyzed E2 (dihydrolipolyl transacetylase). Finally, the oxidized form of lipoamide is regenerated and electrons are transferred to NAD+ in two steps catalyzed by E3 (dihydrolipoyl dehydrogenase). The biochemical details of this reaction have been worked out with alpha ketoglutarate dehydrogenase complex and subunits purified from bovine tissue (McCartney et al. 1998). While all of the human proteins are known as predicted protein products of cloned genes, direct experimental evidence for their functions is available only for E3 (DLD) (Brautigam et al. 2005). 9727038 Pubmed 1998 Subunit interactions in the mammalian alpha-ketoglutarate dehydrogenase complex. Evidence for direct association of the alpha-ketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components. McCartney, RG Rice, JE Sanderson, SJ Bunik, V Lindsay, H Lindsay, JG J Biol Chem 273:24158-64 inferred by electronic annotation IEA GO IEA 6.2.1.4 GDP + Orthophosphate + Succinyl-CoA <=> GTP + Succinate + CoA GDP + Orthophosphate + Succinyl-CoA <=> GTP + Succinate + CoA This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113548 1 Reactome DB_ID: 113525 1 GDP(3-) [ChEBI:58189] GDP(3-) guanosine 5'-diphosphate(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate trianion GDP GDP trianion guanosine 5'-diphosphate ChEBI 58189 Reactome DB_ID: 70958 1 Reactome DB_ID: 113573 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome DB_ID: 29374 1 Reactome DB_ID: 113536 1 succinate(2-) [ChEBI:30031] succinate(2-) succinate (-)OOC-CH2-CH2-COO(-) butanedioic acid, ion(2-) butanedioate ChEBI 30031 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10430603 SUCLG1:SUCLG2 [mitochondrial matrix] SUCLG1:SUCLG2 Reactome DB_ID: 10430000 1 UniProt:A0A6I8S5E0 suclg1 UniProt A0A6I8S5E0 41 EQUAL 346 EQUAL Reactome DB_ID: 10430601 1 UniProt:A0A1B8YAJ2 suclg2 UniProt A0A1B8YAJ2 38 EQUAL 432 EQUAL Reactome Database ID Release 81 10430603 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430603 Reactome R-XTR-156627 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-XTR-156627.1 GO 0004776 GO molecular function Reactome Database ID Release 81 10430604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430604 Reactome Database ID Release 81 10430606 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430606 Reactome R-XTR-71775 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-XTR-71775.1 Mitochondrial succinate CoA ligase (ADP-forming) catalyzes the reversible conversion of succinyl CoA to succinate plus Coenzyme A, coupled to the conversion of ADP and orthophosphate to ATP. The enzyme is a heterodimer containing SUCLG1 and SUCLA2 monomers.<p>The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).<p>Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000). 9765290 Pubmed 1998 Characterization of the ATP- and GTP-specific succinyl-CoA synthetases in pigeon. The enzymes incorporate the same alpha-subunit. Johnson, JD Muhonen, WW Lambeth, DO J Biol Chem 273:27573-9 9765291 Pubmed 1998 Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes Johnson, JD Mehus, JG Tews, KN Milavetz, BI Lambeth, DO J Biol Chem 273:27580-6 13181903 Pubmed 1954 Guanosine triphosphate, the primary product of phosphorylation coupled to the breakdown of succinyl coenzyme A Sanadi, DR Gibson, M Ayengar, P Biochim Biophys Acta 14:434-6 10727444 Pubmed 2000 Interaction between succinyl CoA synthetase and the heme-biosynthetic enzyme ALAS-E is disrupted in sideroblastic anemia Furuyama, K Sassa, S J Clin Invest 105:757-64 17668387 Pubmed 2007 Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion Ostergaard, E Christensen, E Kristensen, E Mogensen, B Duno, M Shoubridge, EA Wibrand, F Am J Hum Genet 81:383-7 15234968 Pubmed 2004 Expression of two succinyl-CoA synthetases with different nucleotide specificities in mammalian tissues Lambeth, DO Tews, KN Adkins, S Frohlich, D Milavetz, BI J Biol Chem 279:36621-4 inferred by electronic annotation IEA GO IEA 6.2.1.5 ADP + Orthophosphate + Succinyl-CoA <=> ATP + Succinate + CoA ADP + Orthophosphate + Succinyl-CoA <=> ATP + Succinate + CoA This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113548 1 Reactome DB_ID: 113581 1 Reactome DB_ID: 70958 1 Reactome DB_ID: 29374 1 Reactome DB_ID: 113536 1 Reactome DB_ID: 113593 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10430006 SUCLA2:SUCLG1 [mitochondrial matrix] SUCLA2:SUCLG1 Reactome DB_ID: 10430000 1 41 EQUAL 346 EQUAL Reactome DB_ID: 10430004 1 UniProt:Q6P4J7 sucla2 UniProt Q6P4J7 53 EQUAL 463 EQUAL Reactome Database ID Release 81 10430006 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430006 Reactome R-XTR-156625 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-XTR-156625.1 GO 0004775 GO molecular function Reactome Database ID Release 81 10430007 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430007 Reactome Database ID Release 81 10430009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430009 Reactome R-XTR-70997 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-XTR-70997.1 Mitochondrial succinate CoA ligase (ADP-forming) catalyzes the reversible conversion of succinyl CoA to succinate plus Coenzyme A, coupled to the conversion of ADP and orthophosphate to ATP. The enzyme is a heterodimer containing SUCLG1 and SUCLA2 monomers.<p>The enzyme catalyzing the reaction in vertebrates is a heterodimer that occurs in two isoforms. The enzymes have been purified from pigeon and rat tissue and characterized in detail. Both isoforms, an alpha:betaA heterodimer and an alpha:betaG heterodimer, catalyze the reversible conversion of succinyl CoA to succinate plus Coenzyme A. The alpha:betaA heterodimer couples this conversion to the synthesis of ATP from ADP and orthophosphate, while the alpha:betaG heterodimer couples it to the synthesis of GTP from GDP and orthophosphate (Johnson et al. 1998a,b; Lambeth et al. 2004). Consistent with these results in model systems, patients homozygous for a mutant allele of the gene encoding the ADP enzyme beta subunit, SUCLA2, are deficient in succinyl CoA ligase activity (Elpeleg et al. 2005).<p>Both isoforms are found in vivo, and appear to be expressed at different levels in various tissues. Their relative contributions to the flux of carbon atoms through the TCA cycle are unknown. Genetic and biochemical data suggest that the alpha:betaA isoform may be required to catalyze the reverse reaction, conversion of succinate, Coenzyme A, and ATP to succinyl CoA, ADP, and orthophosphate for heme biosynthesis (Furuyama and Sassa 2000). 15877282 Pubmed 2005 Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion Elpeleg, O Miller, C Hershkovitz, E Bitner-Glindzicz, M Bondi-Rubinstein, G Rahman, S Pagnamenta, A Eshhar, S Saada, A Am J Hum Genet 76:1081-6 inferred by electronic annotation IEA GO IEA 1.3.5.1 Succinate <=> Fumarate (with FAD redox reaction on enzyme) Succinate <=> Fumarate (with FAD redox reaction on enzyme) This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113536 1 Reactome DB_ID: 113588 1 fumaric acid [ChEBI:18012] fumaric acid ChEBI 18012 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429993 SDH complex (ox.) [mitochondrial inner membrane] SDH complex (ox.) Reactome DB_ID: 10429991 1 UniProt:Q6P355 sdhd UniProt Q6P355 57 EQUAL 159 EQUAL Reactome DB_ID: 10429987 1 UniProt:F6U5J7 sdhc UniProt F6U5J7 30 EQUAL 169 EQUAL Reactome DB_ID: 10429983 1 Succinate dehydrogenase Iron Sulphur (subunit B) [mitochondrial inner membrane] Succinate dehydrogenase Iron Sulphur (subunit B) Reactome DB_ID: 10429981 1 UniProt:B0BM36 sdhb UniProt B0BM36 29 EQUAL 280 EQUAL Reactome DB_ID: 113591 1 Iron Sulphur Cluster [mitochondrial inner membrane] Iron Sulphur Cluster Iron Sulfur Cluster Reactome Database ID Release 81 10429983 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429983 Reactome R-XTR-70987 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-XTR-70987.1 Reactome DB_ID: 10429977 1 Succinate dehydrogenase flavoprotein (subunit A), oxidised [mitochondrial inner membrane] Succinate dehydrogenase flavoprotein (subunit A), oxidised Reactome DB_ID: 113597 1 Reactome DB_ID: 10429975 1 UniProt:Q28ED0 sdha UniProt Q28ED0 44 EQUAL 664 EQUAL Reactome Database ID Release 81 10429977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429977 Reactome R-XTR-70984 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-XTR-70984.1 Reactome Database ID Release 81 10429993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429993 Reactome R-XTR-70990 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-XTR-70990.1 GO 0008177 GO molecular function Reactome Database ID Release 81 10429994 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429994 Reactome Database ID Release 81 10429996 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429996 Reactome R-XTR-70994 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-XTR-70994.1 The succinate dehydrogenase complex (SDH), associated with the inner mitochondrial membrane, catalyzes the dehydrogenation of succinate to fumarate, reducing the FAD cofactor bound to the enzyme. This redox potential is then used in the electron transfer chain to drive a proton motive force to generate ATP.<br>The endogenous metabolite itaconate has been shown to bind and inhibit SDH, leading to an accumulation of succinate. Elevated succinate levels modulate immune, hypoxic and metabolic reprogramming pathways, including during oncogenesis (Booth et al, 1952; Dervertanian et al, 1964; Cordes et al, 2016; Lampropoulou et al, 2016). Studies examining the impact of elevated citric acid cycle intermediates such as succinate and fumarate led to the recognition of the role of metabolites in driving cancer progression ('oncometabolites') (Selak et al, 2005; Pollard et al, 2005; Koivunen et al, 2007; reviewed in Hayashi et al, 2018). 15987702 Pubmed 2005 Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations Pollard, P J Brière, J J Alam, N A Barwell, J Barclay, E Wortham, N C Hunt, T Mitchell, M Olpin, S Moat, S J Hargreaves, I P Heales, S J Chung, Y L Griffiths, J R Dalgleish, A McGrath, J A Gleeson, M J Hodgson, S V Poulsom, R Rustin, P Tomlinson, I P M Hum Mol Genet 14:2231-9 17182618 Pubmed 2007 Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF Koivunen, Peppi Hirsilä, Maija Remes, Anne M Hassinen, Ilmo E Kivirikko, Kari I Myllyharju, Johanna J Biol Chem 282:4524-4532 16143825 Pubmed 2005 Succinate dehydrogenase deficiency in human Briere, JJ Favier, J El Ghouzzi, V Djouadi, F Benit, P Gimenez, AP Rustin, P Cell Mol Life Sci 62:2317–2324 27189937 Pubmed 2016 Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels Cordes, Thekla Wallace, Martina Michelucci, Alessandro Divakaruni, Ajit S Sapcariu, Sean C Sousa, Carole Koseki, Haruhiko Cabrales, Pedro Murphy, Anne N Hiller, Karsten Metallo, Christian M J Biol Chem 291:14274-14284 14946179 Pubmed 1952 The inhibitory effects of itaconic acid in vitro and in vivo BOOTH, A N Taylor, J WILSON, R H DEEDS, F J Biol Chem 195:697-702 15652751 Pubmed 2005 Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase Selak, Mary A Armour, Sean M MacKenzie, Elaine D Boulahbel, Houda Watson, David G Mansfield, Kyle D Pan, Yi Simon, M Celeste Thompson, CB Gottlieb, Eyal Cancer Cell 7:77-85 30844107 Pubmed 2019 Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer Hayashi, Yoshihiro Yokota, Asumi Harada, Hironori Huang, Gang Cancer Sci 110:1510-1517 14249115 Pubmed 1964 STUDIES ON SUCCINATE DEHYDROGENASE. I. SPECTRAL PROPERTIES OF THE PURIFIED ENZYME AND FORMATION OF ENZYME-COMPETITIVE INHIBITOR COMPLEXES DERVARTANIAN, D V VEEGER, C Biochim Biophys Acta 92:233-47 27374498 Pubmed 2016 Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation Lampropoulou, Vicky Sergushichev, Alexey Bambouskova, Monika Nair, Sharmila Vincent, Emma E Loginicheva, Ekaterina Cervantes-Barragan, Luisa Ma, Xiucui Huang, Stanley Ching-Cheng Griss, Takla Weinheimer, Carla J Khader, Shabaana Randolph, Gwendalyn J Pearce, Edward J Jones, Russell G Diwan, Abhinav Diamond, MS Artyomov, Maxim N Cell Metab 24:158-66 inferred by electronic annotation IEA GO IEA 4.2.1.2 Fumarate + H2O <=> (S)-Malate Fumarate + H2O <=> (S)-Malate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113521 1 Reactome DB_ID: 113588 1 Reactome DB_ID: 113544 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429968 FH tetramer [mitochondrial matrix] FH tetramer Reactome DB_ID: 10429966 4 UniProt:A0A6I8RSB2 map1lc3c UniProt A0A6I8RSB2 45 EQUAL 510 EQUAL Reactome Database ID Release 81 10429968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429968 Reactome R-XTR-451041 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-XTR-451041.1 GO 0004333 GO molecular function Reactome Database ID Release 81 10429969 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429969 Reactome Database ID Release 81 10429971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429971 Reactome R-XTR-70982 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-XTR-70982.1 Mitochondrial fumarate hydratase catalyzes the reversible reaction of fumarate and water to form malate, the seventh step of the TCA cycle (Bourgeron et al. 1994). Unpublished crystallographic data indicate that the protein is a tetramer (PDB 3E04). 8200987 Pubmed 1994 Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency Bourgeron, T Chretien, D Poggi-Bach, J Doonan, S Rabier, D Letouzé, P Munnich, A Rötig, A Landrieu, P Rustin, P J Clin Invest 93:2514-2518 inferred by electronic annotation IEA GO IEA 4.2.1.2 (S)-Malate <=> Fumarate + H2O (S)-Malate <=> Fumarate + H2O This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113544 1 Reactome DB_ID: 113521 1 Reactome DB_ID: 113588 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429968 Reactome Database ID Release 81 10458091 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458091 Reactome R-XTR-451033 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-XTR-451033.1 Mitochondrial fumarate hydratase catalyzes the reversible reaction of malate to form fumarate and water (Bourgeron et al. 1994). Unpublished crystallographic data indicate that the protein is a tetramer (PDB 3E04). inferred by electronic annotation IEA GO IEA 1.1.1.37 (S)-Malate + NAD+ <=> Oxaloacetate + NADH + H+ (S)-Malate + NAD+ <=> Oxaloacetate + NADH + H+ This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113544 1 Reactome DB_ID: 113526 1 Reactome DB_ID: 113587 1 Reactome DB_ID: 113529 1 Reactome DB_ID: 29362 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429959 MDH2 dimer [mitochondrial matrix] MDH2 dimer Reactome DB_ID: 10429957 2 UniProt:F6T7F0 mdh2 UniProt F6T7F0 25 EQUAL 338 EQUAL Reactome Database ID Release 81 10429959 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429959 Reactome R-XTR-198511 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-XTR-198511.1 GO 0030060 GO molecular function Reactome Database ID Release 81 10429960 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429960 Reactome Database ID Release 81 10429962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429962 Reactome R-XTR-70979 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-XTR-70979.1 Mitochondrial malate dehydrogenase catalyzes the reversible reaction of malate and NAD+ to form oxaloacetate and NADH + H+ (Luo et al. 2006). This reaction is highly endergonic but is pulled in the direction annotated here when the TCA cycle is operating. Unpublished crystallographic data indicate that the protein is a dimer (PDB 3E04). 16740313 Pubmed 2006 An NADH-tetrazolium-coupled sensitive assay for malate dehydrogenase in mitochondria and crude tissue homogenates Luo, C Wang, X Long, J Liu, J J Biochem Biophys Methods 68:101-11 inferred by electronic annotation IEA GO IEA 1.1.1.37 Oxaloacetate + NADH + H+ <=> (S)-Malate + NAD+ Oxaloacetate + NADH + H+ <=> (S)-Malate + NAD+ This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113587 1 Reactome DB_ID: 113529 1 Reactome DB_ID: 29362 1 Reactome DB_ID: 113544 1 Reactome DB_ID: 113526 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10429959 Reactome Database ID Release 81 10430608 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430608 Reactome R-XTR-71783 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-XTR-71783.1 Mitochondrial malate dehydrogenase catalyzes the reversible reaction of oxaloacetate and NADH + H+ to form malate and NAD+ (Luo et al. 2006). Unpublished crystallographic data indicate that the protein is a dimer (PDB 3E04). 9792106 Pubmed 1998 Aggregation states of mitochondrial malate dehydrogenase Sanchez, SA Hazlett, TL Brunet, JE Jameson, DM Protein Sci 7:2184-2189 inferred by electronic annotation IEA GO IEA 1.1.1.40 1.1.1.38 4.1.1.112 FAHD1:Zn2+ dimer hydrolyses OA to PYR FAHD1:Zn2+ dimer hydrolyses OA to PYR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113587 1 Reactome DB_ID: 29376 1 Reactome DB_ID: 113557 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10517022 FAHD1:Mg2+ dimer [mitochondrial matrix] FAHD1:Mg2+ dimer Reactome DB_ID: 10517020 2 FAHD1:Mg2+ [mitochondrial matrix] FAHD1:Mg2+ Reactome DB_ID: 10517018 1 UniProt:A0A6I8PLR1 fahd1 UniProt A0A6I8PLR1 28 EQUAL 224 EQUAL Reactome DB_ID: 109496 1 Reactome Database ID Release 81 10517020 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517020 Reactome R-XTR-9012015 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-XTR-9012015.1 Reactome Database ID Release 81 10517022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517022 Reactome R-XTR-9012057 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-XTR-9012057.1 GO 0008948 GO molecular function Reactome Database ID Release 81 10517023 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517023 Reactome Database ID Release 81 10517025 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517025 Reactome R-XTR-9012016 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-XTR-9012016.1 Fumarylacetoacetate hydrolase domain containing protein 1 (FAHD1) (Pircher et al. 2011, 2015, Jansen-Duerr et al. 2016) was identified to display a bi-functional catalytic mechanism (Weiss et al. 2018), being able to hydrolyse acylpyruvates (Pircher et al. 2011) similar to fumarylpyruvate hydrolase NagK of <i>Ralstonia sp.</i> (<i>acetylpyruvate</i>: vmax = 0,135 µmol/min/mg, KM = 4,6 µM), and to cleave oxaloacetate (OAA) via decarboxylation (Pircher et al. 2015) (OAA: vmax = 0,21 µmol/min/mg, KM = 32 µM). The enzyme is of dimeric form (Manjasetty et al. 2004) and uses Mg2+ or Mn2+ as cofactor. It is localized in the mitochondrial matrix (Pircher et al. 2011, Trukhina et al. 2002, Di Berardino et al. 1996). Its identification as ODx (Pircher et al. 2015) renders FAHD1 a possible antagonist to pyruvate carboxylase (PC) at a central position in the TCA cycle(Jansen-Duerr et al. 2016). It is believed that the ability of FAHD1 to decarboxylate OAA provides the basis of its requirement for maintaining healthy mitochondria in certain cells and tissues (Taferner et al. 2015, Petit et al. 2017). However, further studies of this topic are warranted. 21878618 Pubmed 2011 Identification of human fumarylacetoacetate hydrolase domain-containing protein 1 (FAHD1) as a novel mitochondrial acylpyruvase Pircher, Haymo Straganz, Grit D Ehehalt, Daniela Morrow, Geneviève Tanguay, Robert M Jansen-Dürr, Pidder J. Biol. Chem. 286:36500-8 15551868 Pubmed 2004 X-ray structure of fumarylacetoacetate hydrolase family member Homo sapiens FLJ36880 Manjasetty, Babu A Niesen, Frank H Delbrück, Heinrich Götz, Frank Sievert, Volker Büssow, Konrad Behlke, Joachim Heinemann, Udo Biol. Chem. 385:935-42 28286170 Pubmed 2017 Depletion of oxaloacetate decarboxylase FAHD1 inhibits mitochondrial electron transport and induces cellular senescence in human endothelial cells Petit, Michele Koziel, Rafal Etemad, Solmaz Pircher, Haymo Jansen-Dürr, Pidder Exp. Gerontol. 92:7-12 25575590 Pubmed 2015 Identification of FAH domain-containing protein 1 (FAHD1) as oxaloacetate decarboxylase Pircher, Haymo von Grafenstein, Susanne Diener, Thomas Metzger, Christina Albertini, Eva Taferner, Andrea Unterluggauer, Hermann Kramer, Christian Liedl, Klaus R Jansen-Dürr, Pidder J. Biol. Chem. 290:6755-62 inferred by electronic annotation IEA GO IEA 1.1.1.38 1.1.1.39 ME2:Mg2+ tetramer oxidatively decarboxylates MAL to PYR ME2:Mg2+ tetramer oxidatively decarboxylates MAL to PYR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113544 1 Reactome DB_ID: 113526 1 Reactome DB_ID: 29376 1 Reactome DB_ID: 113529 1 Reactome DB_ID: 113557 1 Reactome DB_ID: 29362 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10517048 ME2:Mg2+ tetramer [mitochondrial matrix] ME2:Mg2+ tetramer Reactome DB_ID: 10517046 2 ME2:Mg2+ dimer [mitochondrial matrix] ME2:Mg2+ dimer Reactome DB_ID: 10517044 2 ME2:Mg2+ [mitochondrial matrix] ME2:Mg2+ Reactome DB_ID: 10517042 1 UniProt:B7ZUK1 me2 UniProt B7ZUK1 19 EQUAL 584 EQUAL Reactome DB_ID: 109496 1 Reactome Database ID Release 81 10517044 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517044 Reactome R-XTR-9012271 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-XTR-9012271.1 Reactome Database ID Release 81 10517046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517046 Reactome R-XTR-9012259 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-XTR-9012259.1 Reactome Database ID Release 81 10517048 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517048 Reactome R-XTR-9012264 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-XTR-9012264.1 GO 0004471 GO molecular function Reactome Database ID Release 81 10517049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517049 Reactome Database ID Release 81 10517051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517051 Reactome R-XTR-9012268 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-XTR-9012268.1 One hallmark of cancer is altered cellular metabolism. Malic enzymes (MEs) are a family of homotetrameric enzymes that catalyse the reversible oxidative decarboxylation of L-malate to pyruvate, with a simultaneous reduction of NAD(P)+ to NAD(P)H. As MEs generate NADPH and NADH, they may play dual roles in energy production and reductive biosynthesis. Humans possess three ME isoforms; ME1 is cytosolic and utilises NADP+, ME3 is mitochondrial and can utilise NADP+ and ME2 is mitochondrial and can utililse either NAD+ or NADP+ (Chang & Tong 2003).<br><br>Mitochondrial NAD-dependent malic enzyme (ME2, aka m-NAD(P)-ME) oxidatively decarboxylates (s)-malate (MAL) to pyruvate (PYR) and CO2 using NAD+ (or NADP+) as cofactor (Loeber et al. 1991, Tao et al. 2003). ME2 exists as a dimer of dimers and requires a divalent metal such as Mg2+ for catalysis (Chang & Tong 2003, Murugan & Hung 2012). Unlike the other MEs, ME2's enzymatic activity can be allosterically activated by fumarate (FUMA) and inhibited by ATP (Yang et al. 2002). ME2 could play a critical role in cutaneous melanoma progression, the most life-threatening neoplasm of the skin. Targeting ME2 could be a novel approach to inhibiting melanoma cell proliferation and growth (Chang et al. 2015). ME2 has also been demonstrated to be involved in glioblastoma multiforme (GBM) growth, invasion and migration. Inhibition of ME2 could potentially be therapeutic in the treatment of GBM (Cheng et al. 2016). 27166188 Pubmed 2016 The mechanisms of malic enzyme 2 in the tumorigenesis of human gliomas Cheng, Chiao-Pei Huang, Li-Chun Chang, Yung-Lung Hsieh, Ching-Hsuan Huang, Shih-Ming Hueng, Dueng-Yuan Oncotarget 7:41460-41472 1993674 Pubmed 1991 Human NAD(+)-dependent mitochondrial malic enzyme. cDNA cloning, primary structure, and expression in Escherichia coli Loeber, G Infante, A A Maurer-Fogy, I Krystek, E Dworkin, M B J. Biol. Chem. 266:3016-21 12121650 Pubmed 2002 Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate Yang, Zhiru Lanks, Charles W Tong, L Structure 10:951-60 12962632 Pubmed 2003 Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism Tao, Xiao Yang, Zhiru Tong, L Structure 11:1141-50 25202825 Pubmed 2015 Human mitochondrial NAD(P)(+)-dependent malic enzyme participates in cutaneous melanoma progression and invasion Chang, Yung-Lung Gao, Hong-Wei Chiang, Chien-Ping Wang, Wei-Ming Huang, Shih-Ming Ku, Chien-Fen Liu, Guang-Yaw Hung, Hui-Chih J. Invest. Dermatol. 135:807-15 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 81 9012256 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9012256 Reactome R-HSA-9012256 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-9012256.1 Reactome DB_ID: 113588 INHIBITION Reactome Database ID Release 81 9012284 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9012284 Reactome R-HSA-9012284 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-9012284.1 Reactome DB_ID: 113593 1.1.1.40 ME3:Mg2+ tetramer oxidatively decarboxylates MAL to PYR ME3:Mg2+ tetramer oxidatively decarboxylates MAL to PYR This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113563 1 Reactome DB_ID: 113544 1 Reactome DB_ID: 29376 1 Reactome DB_ID: 113529 1 Reactome DB_ID: 113557 1 Reactome DB_ID: 113600 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10517076 ME3:Mg2+ tetramer [mitochondrial matrix] ME3:Mg2+ tetramer Reactome DB_ID: 10517074 2 ME3:Mg2+ dimer [mitochondrial matrix] ME3:Mg2+ dimer Reactome DB_ID: 10517072 2 ME3:Mg2+ [mitochondrial matrix] ME3:Mg2+ Reactome DB_ID: 109496 1 Reactome DB_ID: 10517070 1 UniProt:A0A6I8Q7X5 me3 UniProt A0A6I8Q7X5 1 EQUAL 604 EQUAL Reactome Database ID Release 81 10517072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517072 Reactome R-XTR-9012355 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-XTR-9012355.1 Reactome Database ID Release 81 10517074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517074 Reactome R-XTR-9012350 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-XTR-9012350.1 Reactome Database ID Release 81 10517076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517076 Reactome R-XTR-9012356 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-XTR-9012356.1 Reactome Database ID Release 81 10517077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517077 Reactome Database ID Release 81 10517079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517079 Reactome R-XTR-9012349 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-XTR-9012349.1 One hallmark of cancer is altered cellular metabolism. Malic enzymes (MEs) are a family of homotetrameric enzymes that catalyse the reversible oxidative decarboxylation of L-malate to pyruvate, with a simultaneous reduction of NAD(P)+ to NAD(P)H. As MEs generate NADPH and NADH, they may play roles in energy production and reductive biosynthesis. Humans possess three ME isoforms; ME1 is cytosolic and utilises NADP+, ME3 is mitochondrial and can utilise NADP+ and ME2 is mitochondrial and can utililse either NAD+ or NADP+ (Chang & Tong 2003, Murugan & Hung 2012).<br><br>NADP-dependent malic enzyme (ME3, aka m-NADP-ME) is a mitochondrial enzyme that oxidatively decarboxylates (s)-malate (MAL) to pyruvate (PYR) and CO2 using NADP+ as cofactor (Loeber et al. 1994). ME1 exists as a dimer of dimers (Murugan & Hung 2012) and a divalent metal such as Mg2+ is essential for catalysis (Chang & Tong 2003). ME3 may play a role in insulin secretion (Hasan et al. 2015) but how it does this in panceratic beta cells has not been established yet. 25594249 Pubmed 2015 Mitochondrial malic enzyme 3 is important for insulin secretion in pancreatic β-cells Hasan, Noaman M Longacre, Melissa J Stoker, Scott W Kendrick, Mindy A MacDonald, Michael J Mol. Endocrinol. 29:396-410 7818469 Pubmed 1994 Purification, cDNA cloning and heterologous expression of the human mitochondrial NADP(+)-dependent malic enzyme Loeber, G Maurer-Fogy, I Schwendenwein, R Biochem. J. 304:687-92 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10522420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10522420 Reactome R-XTR-71403 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-XTR-71403.1 GO 0006099 GO biological process In the citric acid or tricarboxylic acid (TCA) cycle, the acetyl group of acetyl CoA (derived primarily from oxidative decarboxylation of pyruvate, beta-oxidation of long-chain fatty acids, and catabolism of ketone bodies and several amino acids) can be completely oxidized to CO2 in reactions that also yield one high-energy phosphate bond (as GTP or ATP) and four reducing equivalents (three NADH + H+, and one FADH2). The NADH and FADH2 are then oxidized by the electron transport chain to yield nine more high-energy phosphate bonds (as ATP). All reactions of the citric acid cycle take place in the mitochondrion.<p>Eight canonical reactions mediate the synthesis of citrate from acetyl-CoA and oxaloacetate and the metabolism of citrate to re-form oxaloacetate. Six additional reactions are included here. Three reversible reactions, the interconversions of citrate and isocitrate, of fumarate and malate, and of malate and oxaloacetate are annotated in both their canonical (forward) and reverse directions. The synthesis of succinate from succinyl-CoA can be coupled to the phosphorylation of either GDP (the canonical reaction) or ADP; both reactions are annotated. Two mitochondrial isocitrate dehydrogenase isozymes catalyze the oxidative decarboxylation of isocitrate to form alpha-ketoglutarate (2-oxoglutarate): IDH3 catalyzes the canonical reaction coupled to the reduction of NAD+, while IDH2 catalyzes the same reaction coupled to reduction of NADP+, a reaction whose normal physiological function is unclear. Both reactions are annotated. Finally, a reaction is annotated in which reducing equivalents are transferred from NADPH to NAD+ coupled to proton import across the inner mitochondrial membrane.<p>The cyclical nature of the reactions responsible for the oxidation of acetate was first suggested by Hans Krebs, from biochemical studies of pigeon breast muscle (Krebs et al. 1938; Krebs and Eggleston 1940). Many of the molecular details of individual reactions were worked out by Ochoa and colleagues, largely through studies of enzymes purified from pig heart (Ochoa 1980). While the human homologues of these enzymes have all been identified, their biochemical characterization has in general been limited and many molecular details of the human reactions are inferred from those worked out in studies of the model systems. 16747180 Pubmed 1940 The oxidation of pyruvate in pigeon breast muscle Krebs, HA Eggleston, LV Biochem J 34:442-459 16746585 Pubmed 1938 The formation of citric and alpha-ketoglutaric acids in the mammalian body Krebs, HA Salvin, E Johnson, WA Biochem J 32:113-117 6773467 Pubmed 1980 The pursuit of a hobby Ochoa, S Annu Rev Biochem 49:1-30 inferred by electronic annotation IEA GO IEA Interconversion of 2-oxoglutarate and 2-hydroxyglutarate Interconversion of 2-oxoglutarate and 2-hydroxyglutarate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 1.1.99.2 (S)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 (S)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113596 1 Reactome DB_ID: 880013 1 (S)-2-hydroxyglutaric acid [ChEBI:32797] (S)-2-hydroxyglutaric acid ChEBI 32797 Reactome DB_ID: 113594 1 Reactome DB_ID: 31649 1 FADH2(2-) [ChEBI:58307] FADH2(2-) 1,5-dihydro-FAD dianion 1,5-dihydro-FAD(2-) (2R,3S,4S)-5-{7,8-dimethyl-2,4-dioxo-1H,2H,3H,4H,5H,10H-benzo[g]pteridin-10-yl}-2,3,4-trihydroxypentyl ({[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphonato}oxy)phosphonate FADH2 dianion dihydroflavin adenine dinucleotide dianion adenosine 5'-(3-{D-ribo-5-[7,8-dimethyl-2,4-dioxo-1,3,4,5-tetrahydrobenzo[g]pteridin-10(2H)-yl]-2,3,4-trihydroxypentyl} diphosphate) FADH2 dihydroflavin adenine dinucleotide(2-) ChEBI 58307 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10460183 UniProt:F6QMX5 l2hgdh UniProt F6QMX5 52 EQUAL 463 EQUAL GO 0047545 GO molecular function Reactome Database ID Release 81 10460184 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460184 Reactome Database ID Release 81 10460186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460186 Reactome R-XTR-880050 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-XTR-880050.1 L2HDGH associated with the mitochondrial inner membrane catalyzes the FAD-dependent reaction of (S)-2-hydroxyglutarate to form 2-oxoglutarate (Rzem et al. 2006). L2HDGH mutations are associated with high levels of (S)-2-hydroxyglutarate in vivo and variable neurological symptoms (Rzem et al. 2004; Topcu et al. 2004). 16005139 Pubmed 2006 The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase Rzem, R Van Schaftingen, Emile Veiga-da-Cunha, M Biochimie 88:113-6 15548604 Pubmed 2004 A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria Rzem, R Veiga-da-Cunha, M Noel, G Goffette, S Nassogne, MC Tabarki, B Scholler, C Marquardt, T Vikkula, M Van Schaftingen, Emile Proc Natl Acad Sci U S A 101:16849-54 15385440 Pubmed 2004 L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1 Topçu, M Jobard, F Halliez, S Coskun, T Yalçinkayal, C Gerceker, FO Wanders, Ronald J A Prud'homme, JF Lathrop, M Ozguc, M Fischer, J Hum Mol Genet 13:2803-11 inferred by electronic annotation IEA GO IEA 1.1.99.39 (R)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 (R)-2-hydroxyglutarate + FAD => 2-oxoglutarate + FADH2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113596 1 Reactome DB_ID: 879997 1 (R)-2-hydroxyglutaric acid [ChEBI:32796] (R)-2-hydroxyglutaric acid (R)-2-Hydroxyglutarate ChEBI 32796 Reactome DB_ID: 113594 1 Reactome DB_ID: 31649 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10460174 UniProt:A0A6I8SE28 d2hgdh UniProt A0A6I8SE28 14 EQUAL 521 EQUAL GO 0051990 GO molecular function Reactome Database ID Release 81 10460175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460175 Reactome Database ID Release 81 10460177 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460177 Reactome R-XTR-880007 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-XTR-880007.1 D2HDGH associated with the mitochondrial inner membrane catalyzes the FAD-dependent reaction of (R)-2-hydroxyglutarate to form 2-oxoglutarate (Achouri et al. 2004). D2HDGH mutations are associated with high levels of (R)-2-hydroxyglutarate in vivo and variable neurological symptoms (Struys et al. 2005; Wanders and Mooyer 1995)). 7564244 Pubmed 1995 D-2-hydroxyglutaric acidaemia: identification of a new enzyme, D-2-hydroxyglutarate dehydrogenase, localized in mitochondria Wanders, Ronald J A Mooyer, P J Inherit Metab Dis 18:194-6 15070399 Pubmed 2004 Identification of a dehydrogenase acting on D-2-hydroxyglutarate Achouri, Y Noel, G Vertommen, Didier Rider, MH Veiga-da-Cunha, M Van Schaftingen, Emile Biochem J 381:35-42 16435184 Pubmed 2005 Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias Struys, Eduard A Verhoeven, Nanda M Ten Brink, HJ Wickenhagen, WV Gibson, KM Jakobs, Cornelis J Inherit Metab Dis 28:921-30 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 81 880068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880068 Reactome R-HSA-880068 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-880068.1 Reactome DB_ID: 113527 ACTIVATION Reactome Database ID Release 81 880065 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880065 Reactome R-HSA-880065 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-880065.1 Reactome DB_ID: 880067 ACTIVATION Reactome Database ID Release 81 880066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880066 Reactome R-HSA-880066 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-880066.1 Reactome DB_ID: 880069 cobalt atom [ChEBI:27638] cobalt atom ChEBI 27638 1.1.99.24 (R)-2-hydroxyglutarate + succinate semialdehyde <=> 2-oxoglutarate + 4-hydroxybutyrate (R)-2-hydroxyglutarate + succinate semialdehyde <=> 2-oxoglutarate + 4-hydroxybutyrate This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 880046 1 4-oxobutanoate [ChEBI:57706] 4-oxobutanoate succinate semialdehyde ChEBI 57706 Reactome DB_ID: 879997 1 Reactome DB_ID: 880041 1 4-hydroxybutyrate [ChEBI:16724] 4-hydroxybutyrate 4-hydroxybutanoate gamma-hydroxybutyrate ChEBI 16724 Reactome DB_ID: 113594 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10460167 UniProt:A0A7D9NK53 adhfe1 UniProt A0A7D9NK53 GO 0047988 GO molecular function Reactome Database ID Release 81 10460168 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460168 Reactome Database ID Release 81 10460170 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460170 Reactome R-XTR-880002 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-XTR-880002.1 ADHFE1 catalyzes the reversible reaction of (R)-2-hydroxyglutarate and succinate semialdehyde to form 2-oxoglutarate and 4-hydroxybutyrate (Struys et al. 2005). The localization of human ADHFE1 to the mitochondrial matrix is inferred from the location determined experimentally for its rat homolog (Kaufman et al. 1988). 3182820 Pubmed 1988 Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitochondria Kaufman, EE Nelson, T Fales, HM Levin, DM J Biol Chem 263:16872-9 inferred by electronic annotation IEA GO IEA 1.1.99.24 2-oxoglutarate + 4-hydroxybutyrate <=> (R)-2-hydroxyglutarate + succinate semialdehyde 2-oxoglutarate + 4-hydroxybutyrate <=> (R)-2-hydroxyglutarate + succinate semialdehyde This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 880041 1 Reactome DB_ID: 113594 1 Reactome DB_ID: 880046 1 Reactome DB_ID: 879997 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10460167 Reactome Database ID Release 81 10460179 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460179 Reactome R-XTR-880033 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-XTR-880033.1 ADHFE1 catalyzes the reversible reaction of 2-oxoglutarate and 4-hydroxybutyrate to form (R)-2-hydroxyglutarate and succinate semialdehyde (Struys et al. 2005). The localization of human ADHFE1 to the mitochondrial matrix is inferred from the location determined experimentally for its rat homolog (Kaufman et al. 1988). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10524162 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10524162 Reactome R-XTR-880009 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-XTR-880009.1 GO 0006103 GO biological process The two stereoisomers of 2-hydroxyglutarate are normally converted to 2-oxoglutarate in the mitochondrial matrix, and can then be metabolized by the citric acid cycle. The physiological sources of 2-hydroxyglutarate have not been established although plausible hypotheses are that it is generated by lysine breakdown or as a byproduct of delta-aminolevulinate metabolism. The stereoisomers are oxidized to 2-oxoglutarate in FAD-dependent reactions catalyzed by the enzymes D2HGDH (specific for R(-)-2-hydroxyglutarate) and L2HGDH (specific for S(-)-2-hydroxyglutarate). An inherited deficiency in either enzyme is associated with accumulation of 2-hydroxyglutarate and variable neurological symptoms. R(-)-2-hydroxyglutarate also reacts reversibly with succinate semialdehyde to form 4-hydroxybutyrate and 2-oxoglutarate, catalyzed by ADHFE1. No deficiencies of this enzyme have been found in patients with elevated 2-hydroxyglutarate levels (Struys 2006). 18772396 Pubmed 2008 An integrated genomic analysis of human glioblastoma multiforme Parsons, DW Jones, S Zhang, X Lin, JC Leary, RJ Angenendt, P Mankoo, P Carter, H Siu, IM Gallia, GL Olivi, A McLendon, R Rasheed, BA Keir, S Nikolskaya, T Nikolsky, Y Busam, DA Tekleab, H Diaz Jr, LA Hartigan, J Smith, DR Strausberg, RL Marie, SK Shinjo, SM Yan, H Riggins, GJ Bigner, DD Karchin, R Papadopoulos, N Parmigiani, G Vogelstein, B Velculescu, VE Kinzler, KW Science 321:1807-12 16601864 Pubmed 2006 D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect Struys, Eduard A J Inherit Metab Dis 29:21-9 19935646 Pubmed 2009 Cancer-associated IDH1 mutations produce 2-hydroxyglutarate Dang, L White, DW Gross, S Bennett, BD Bittinger, MA Driggers, EM Fantin, VR Jang, HG Jin, S Keenan, MC Marks, KM Prins, RM Ward, PS Yen, KE Liau, LM Rabinowitz, JD Cantley, Lewis C Thompson, CB Vander Heiden, MG Su, SM Nature 462:739-44 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10522388 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10522388 Reactome R-XTR-71406 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-XTR-71406.1 GO 0044237 GO biological process Pyruvate metabolism and the citric acid (TCA) cycle together link the processes of energy metabolism in a human cell with one another and with key biosynthetic reactions. Pyruvate, derived from the reversible oxidation of lactate or transamination of alanine, can be converted to acetyl CoA. Other sources of acetyl CoA include breakdown of free fatty acids and ketone bodies in the fasting state. Acetyl CoA can enter the citric acid cycle, a major source of reducing equivalents used to synthesize ATP, or enter biosynthetic pathways.<p>In addition to its role in energy generation, the citric acid cycle is a source of carbon skeletons for amino acid metabolism and other biosynthetic processes. One such process included here is the interconversion of 2-hydroxyglutarate, probably derived from porphyrin and amino acid metabolism, and 2-oxoglutarate (alpha-ketoglutarate), a citric acid cycle intermediate. inferred by electronic annotation IEA GO IEA Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Respiratory electron transport Respiratory electron transport This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Complex I biogenesis Complex I biogenesis This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> NUBPL binds 4Fe-4S NUBPL binds 4Fe-4S This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 169274 1 4Fe-4S [mitochondrial matrix] 4Fe-4S 4Iron-4Sulfur Cluster Reactome DB_ID: 10497049 1 UniProt:Q0P4L5 nubpl UniProt Q0P4L5 39 EQUAL 319 EQUAL Reactome DB_ID: 10497051 1 NUBPL:4Fe-4S [mitochondrial matrix] NUBPL:4Fe-4S Reactome DB_ID: 169274 1 Reactome DB_ID: 10497049 1 39 EQUAL 319 EQUAL Reactome Database ID Release 81 10497051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10497051 Reactome R-XTR-5690007 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-XTR-5690007.1 Reactome Database ID Release 81 10497053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10497053 Reactome R-XTR-5690023 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-XTR-5690023.1 The iron-sulfur protein NUBPL is thought to bind the cofactor [4Fe-4S] cluster and deliver it to complex I (NADH dehydrogenase) subunits during its biogenesis. The exact mechanism of transfer is unknown but defects in NUBPL are shown to cause mitochondrial complex I deficiency (MT-C1D) with a distinct MRI pattern (Sheftel et al. 2009, Kevelam et al. 2013). 19752196 Pubmed 2009 Human ind1, an iron-sulfur cluster assembly factor for respiratory complex I Sheftel, Alex D Stehling, Oliver Pierik, Antonio J Netz, Daili J A Kerscher, Stefan Elsässer, Hans-Peter Wittig, Ilka Balk, Janneke Brandt, Ulrich Lill, R Mol. Cell. Biol. 29:6059-73 23553477 Pubmed 2013 NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern Kevelam, Sietske H Rodenburg, Richard J Wolf, Nicole I Ferreira, Patrick Lunsing, Roelineke J Nijtmans, Leo G Mitchell, Anne Arroyo, Hugo A Rating, Dietz Vanderver, Adeline van Berkel, CG Abbink, Truus E M Heutink, Peter van der Knaap, Marjo S Neurology 80:1577-83 inferred by electronic annotation IEA GO IEA NUBPL transfers 4Fe-4S to Complex I subunits NUBPL transfers 4Fe-4S to Complex I subunits This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10497051 1 Converted from EntitySet in Reactome Reactome DB_ID: 10500256 1 NDUF subunits [mitochondrial matrix] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ndufs8 [mitochondrial matrix] ndufs7 [mitochondrial matrix] ndufs2 [mitochondrial matrix] UniProt A0A6I8SP86 UniProt F6ZTQ5 UniProt A0A6I8PZD9 Reactome DB_ID: 10497049 1 39 EQUAL 319 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10500258 1 NDUF:4Fe-4S subunits [mitochondrial matrix] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 10500260 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10500260 Reactome R-XTR-6788523 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-XTR-6788523.1 In total, eight iron-sulfur (4Fe-4S) clusters are incorporated into six subunits (mitochondrial matrix-located NDUFS1, S2, S7, S8 and mitochondrial membrane-located V1 and V2) (Andrews et al. 2013). Incorporation into NDUFV1 and V2 (located on the mitochondrial membrane) is shown in a separate reaction. The mechanism of transfer in all cases is unknown. 24191001 Pubmed 2013 Assembly factors for the membrane arm of human complex I Andrews, Byron Carroll, Joe Ding, Shujing Fearnley, Ian M Walker, JE Proc. Natl. Acad. Sci. U.S.A. 110:18934-9 inferred by electronic annotation IEA GO IEA NUBPL transfers 4Fe-4S to NDUFV1, V2 NUBPL transfers 4Fe-4S to NDUFV1, V2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10497051 2 Reactome DB_ID: 10437945 1 UniProt:Q28HQ2 ndufv2 UniProt Q28HQ2 33 EQUAL 249 EQUAL Reactome DB_ID: 10437939 1 UniProt:F6WDT0 me1 UniProt F6WDT0 21 EQUAL 464 EQUAL Reactome DB_ID: 76629 1 FMN(3-) [ChEBI:58210] FMN(3-) flavin mononucleotide trianion riboflavin 5'-monophosphate(3-) riboflavin 5'-phosphate trianion flavin mononucleotide(3-) FMN 1-deoxy-1-(7,8-dimethyl-2,4-dioxo-2H-benzo[g]pteridin-3-id-10(4H)-yl)-5-O-phosphonato-D-ribitol riboflavin 5'-monophosphate trianion 7,8-dimethyl-2,4-dioxo-10-[(2S,3S,4R)-2,3,4-trihydroxy-5-(phosphonatooxy)pentyl]-2H,3H,4H,10H-benzo[g]pteridin-3-ide FMN trianion riboflavin 5'-phosphate(3-) ChEBI 58210 Reactome DB_ID: 10437941 1 NDUFV1:4Fe-4S:FMN [mitochondrial inner membrane] NDUFV1:4Fe-4S:FMN Reactome DB_ID: 10437939 1 21 EQUAL 464 EQUAL Reactome DB_ID: 76629 1 Reactome DB_ID: 164292 1 4Fe-4S [mitochondrial inner membrane] 4Fe-4S 4Iron-4Sulfur Cluster Reactome Database ID Release 81 10437941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437941 Reactome R-XTR-6788516 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-XTR-6788516.1 Reactome DB_ID: 10497049 2 39 EQUAL 319 EQUAL Reactome DB_ID: 10437947 1 NDUFV2:4Fe-4S [mitochondrial inner membrane] NDUFV2:4Fe-4S Reactome DB_ID: 10437945 1 33 EQUAL 249 EQUAL Reactome DB_ID: 164292 1 Reactome Database ID Release 81 10437947 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437947 Reactome R-XTR-6788524 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-XTR-6788524.1 Reactome Database ID Release 81 10500262 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10500262 Reactome R-XTR-6788556 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-XTR-6788556.1 In total, eight iron-sulfur (4Fe-4S) clusters are incorporated into six subunits (mitochondrial matrix-located NDUFS1, S2, S7, S8 and mitochondrial membrane-located V1 and V2) (Andrews et al. 2013). Incorporation into NDUFS1, S2, S7 and S8 is shown in a separate reaction. The mechanism of transfer is unknown. NDUFV1 also binds FMN (Schuelke et al. 1998). 9571201 Pubmed 1998 Cloning of the human mitochondrial 51 kDa subunit (NDUFV1) reveals a 100% antisense homology of its 3'UTR with the 5'UTR of the gamma-interferon inducible protein (IP-30) precursor: is this a link between mitochondrial myopathy and inflammation? Schuelke, M Loeffen, J Mariman, E Smeitink, J van den Heuvel, L Biochem. Biophys. Res. Commun. 245:599-606 inferred by electronic annotation IEA GO IEA NDUF subunits bind to form the IP subcomplex NDUF subunits bind to form the IP subcomplex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10503508 1 NDUFAF7:NDUFS2:2x4Fe-4S [mitochondrial matrix] NDUFAF7:NDUFS2:2x4Fe-4S Reactome DB_ID: 10503506 1 UniProt:Q5BKM6 ndufaf7 UniProt Q5BKM6 47 EQUAL 441 EQUAL Reactome DB_ID: 10438089 1 NDUFS2:4Fe-4S [mitochondrial matrix] NDUFS2:4Fe-4S Reactome DB_ID: 169274 1 Reactome DB_ID: 10438087 1 UniProt:A0A6I8PZD9 ndufs2 34 EQUAL 463 EQUAL Reactome Database ID Release 81 10438089 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438089 Reactome R-XTR-5690027 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-XTR-5690027.1 Reactome Database ID Release 81 10503508 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503508 Reactome R-XTR-164288 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-XTR-164288.1 Reactome DB_ID: 10438099 1 NDUFS7:4Fe-4S [mitochondrial matrix] NDUFS7:4Fe-4S Reactome DB_ID: 10438097 1 UniProt:F6ZTQ5 ndufs7 39 EQUAL 213 EQUAL Reactome DB_ID: 169274 1 Reactome Database ID Release 81 10438099 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438099 Reactome R-XTR-164293 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-XTR-164293.1 Reactome DB_ID: 10438105 1 NDUFS8:2x4Fe-4S [mitochondrial matrix] NDUFS8:2x4Fe-4S Reactome DB_ID: 10438103 1 UniProt:A0A6I8SP86 ndufs8 35 EQUAL 210 EQUAL Reactome DB_ID: 169274 2 Reactome Database ID Release 81 10438105 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438105 Reactome R-XTR-164295 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-XTR-164295.1 Reactome DB_ID: 10438083 1 NDUFA9:FAD [mitochondrial matrix] NDUFA9:FAD Reactome DB_ID: 113596 1 Reactome DB_ID: 10438081 1 UniProt:A0A6I8QSQ5 ndufa9 UniProt A0A6I8QSQ5 36 EQUAL 377 EQUAL Reactome Database ID Release 81 10438083 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438083 Reactome R-XTR-164289 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-XTR-164289.1 Reactome DB_ID: 10438093 1 UniProt:Q6P613 ndufs3 UniProt Q6P613 37 EQUAL 264 EQUAL Reactome DB_ID: 10503510 1 IP subcomplex [mitochondrial matrix] IP subcomplex Reactome DB_ID: 10503508 1 Reactome DB_ID: 10438099 1 Reactome DB_ID: 10438105 1 Reactome DB_ID: 10438083 1 Reactome DB_ID: 10438093 1 37 EQUAL 264 EQUAL Reactome Database ID Release 81 10503510 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503510 Reactome R-XTR-5689699 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-XTR-5689699.1 Reactome Database ID Release 81 10504656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10504656 Reactome R-XTR-6800868 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-XTR-6800868.1 The subunits NDUFS7, S8 and A9, together with NDUFS2 and S3, form an evolutionarily conserved hydrogenase module as part of the Iron-Sulfur protein fraction (IP) subcomplex (Mckenzie & Ryan 2010, Andrews et al. 2013). 20552642 Pubmed 2010 Assembly factors of human mitochondrial complex I and their defects in disease McKenzie, Matthew Ryan, Michael T IUBMB Life 62:497-502 inferred by electronic annotation IEA GO IEA IP subcomplex binds NDUFAF3, NDUFAF4, TIMMDC1 to form Intermediate 1 IP subcomplex binds NDUFAF3, NDUFAF4, TIMMDC1 to form Intermediate 1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10503518 1 UniProt:B5DEA5 ndufaf4 UniProt B5DEA5 1 EQUAL 175 EQUAL Reactome DB_ID: 10503514 1 UniProt:Q6DFN1 ndufaf3 UniProt Q6DFN1 1 EQUAL 184 EQUAL Reactome DB_ID: 10503522 1 UniProt:A0A803JQK5 UniProt A0A803JQK5 1 EQUAL 285 EQUAL Reactome DB_ID: 10503510 1 Reactome DB_ID: 10503524 1 Intermediate 1 [mitochondrial inner membrane] Intermediate 1 Reactome DB_ID: 10503518 1 1 EQUAL 175 EQUAL Reactome DB_ID: 10503514 1 1 EQUAL 184 EQUAL Reactome DB_ID: 10503522 1 1 EQUAL 285 EQUAL Reactome DB_ID: 10503510 1 Reactome Database ID Release 81 10503524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503524 Reactome R-XTR-6788529 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-XTR-6788529.1 Reactome Database ID Release 81 10503588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503588 Reactome R-XTR-6799203 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-XTR-6799203.1 Complex I assembly begins with the formation of a 315kDa subcomplex, centred around the core subunits NADH dehydrogenase [ubiquinone] iron-sulfur proteins 2 and 3 (NDUFS2 and NDUFS3) (Mckenzie & Ryan 2010, Mimaki et al. 2012, Andrews et al. 2013). NDUFS2 is thought to be bound to NDUFAF7 (Carilla-Latorre et al. 2010). Defects in NDUFS2 can cause mitochondrial complex I deficiency (MT-C1D; OMIM:252010), causing a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders (Loeffen et al. 2001). As an initial part of the 315kDa subcomplex, the subunits NDUFS7, S8 and A9, together with NDUFS2 and S3, form an evolutionarily conserved hydrogenase module as part of the Iron-Sulfur protein fraction (IP) subcomplex (termed Intermediate 1 here) (Mckenzie & Ryan 2010, Andrews et al. 2013). 21924235 Pubmed 2012 Understanding mitochondrial complex I assembly in health and disease Mimaki, Masakazu Wang, Xiaonan McKenzie, Matthew Thorburn, David R Ryan, Michael T Biochim. Biophys. Acta 1817:851-62 11220739 Pubmed 2001 Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy Loeffen, J Elpeleg, O Smeitink, J Smeets, R Stöckler-Ipsiroglu, S Mandel, H Sengers, R Trijbels, F van den Heuvel, L Ann. Neurol. 49:195-201 20406883 Pubmed 2010 MidA is a putative methyltransferase that is required for mitochondrial complex I function Carilla-Latorre, Sergio Gallardo, M Esther Annesley, Sarah J Calvo-Garrido, Javier Graña, Osvaldo Accari, Sandra L Smith, Paige K Valencia, A Garesse, Rafael Fisher, Paul R Escalante, Ricardo J. Cell. Sci. 123:1674-83 inferred by electronic annotation IEA GO IEA Intermediate 2 binds MT-ND1:NDUFAF5:NDUFAF6 to form a 315kDa subcomplex Intermediate 2 binds MT-ND1:NDUFAF5:NDUFAF6 to form a 315kDa subcomplex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10503526 1 Intermediate 2 [mitochondrial inner membrane] Intermediate 2 Reactome DB_ID: 10503524 1 Reactome DB_ID: 10438077 1 HP subcomplex [mitochondrial inner membrane] HP subcomplex Reactome DB_ID: 10438041 1 UniProt:Q0VFA9 ndufb9 UniProt Q0VFA9 2 EQUAL 179 EQUAL Reactome DB_ID: 10438001 1 UniProt:A4IH72 ndufa2 UniProt A4IH72 2 EQUAL 99 EQUAL Reactome DB_ID: 10438027 1 UniProt:A4QNM1 ndufb4 UniProt A4QNM1 2 EQUAL 129 EQUAL Reactome DB_ID: 10438053 1 UniProt:A0A1B8Y3G3 ndufc2 UniProt A0A1B8Y3G3 1 EQUAL 119 EQUAL Reactome DB_ID: 10438005 1 UniProt:A0A6I8SQC4 ndufa3 UniProt A0A6I8SQC4 2 EQUAL 84 EQUAL Reactome DB_ID: 10438013 1 Ghost homologue of NDUFA8 [mitochondrial inner membrane] Ghost homologue of NDUFA8 Reactome DB_ID: 10438067 1 NDUFA10:FAD [mitochondrial inner membrane] NDUFA10:FAD Reactome DB_ID: 113597 1 Reactome DB_ID: 10438065 1 Ghost homologue of NDUFA10 [mitochondrial inner membrane] Ghost homologue of NDUFA10 Reactome Database ID Release 81 10438067 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438067 Reactome R-XTR-164294 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-XTR-164294.1 Reactome DB_ID: 10438035 1 UniProt:A4II52 ndufb7 UniProt A4II52 2 EQUAL 137 EQUAL Reactome DB_ID: 10438057 1 UniProt:A0A803JG20 ndufa13 UniProt A0A803JG20 2 EQUAL 144 EQUAL Reactome DB_ID: 10437997 1 UniProt:A0A803JX78 ndufa1 UniProt A0A803JX78 1 EQUAL 70 EQUAL Reactome DB_ID: 10438011 1 UniProt:A0A803JVE2 UniProt A0A803JVE2 2 EQUAL 113 EQUAL Reactome DB_ID: 10438045 1 UniProt:A4QNF0 elp6 UniProt A4QNF0 1 EQUAL 172 EQUAL Reactome DB_ID: 10438061 1 UniProt:B3DM83 ndufa11 UniProt B3DM83 2 EQUAL 141 EQUAL Reactome DB_ID: 10438017 1 UniProt:Q6AZL3 ndufab1 UniProt Q6AZL3 69 EQUAL 156 EQUAL Reactome DB_ID: 10438031 1 UniProt:F6V6L5 ndufb5 UniProt F6V6L5 47 EQUAL 189 EQUAL Reactome DB_ID: 10438071 1 UniProt:A0A803J5X2 ndufb1 UniProt A0A803J5X2 1 EQUAL 58 EQUAL Reactome DB_ID: 10438021 1 UniProt:F7A0M7 ndufb2 UniProt F7A0M7 34 EQUAL 105 EQUAL Reactome DB_ID: 10438049 1 UniProt:A0A6I8PY53 UniProt A0A6I8PY53 28 EQUAL 76 EQUAL Reactome DB_ID: 10438063 1 Ghost homologue of NDUFB11 [mitochondrial inner membrane] Ghost homologue of NDUFB11 Reactome DB_ID: 10438037 1 Ghost homologue of NDUFB8 [mitochondrial inner membrane] Ghost homologue of NDUFB8 Reactome DB_ID: 10438075 1 UniProt:Q28BN5 ndufa5 UniProt Q28BN5 2 EQUAL 116 EQUAL Reactome DB_ID: 10438023 1 Ghost homologue of NDUFB3 [mitochondrial inner membrane] Ghost homologue of NDUFB3 Reactome DB_ID: 10438007 1 Ghost homologue of NDUFA6 [mitochondrial inner membrane] Ghost homologue of NDUFA6 Reactome Database ID Release 81 10438077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438077 Reactome R-XTR-163929 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-XTR-163929.1 Reactome Database ID Release 81 10503526 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503526 Reactome R-XTR-6799181 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-XTR-6799181.1 Reactome DB_ID: 10503530 1 UniProt:A0A6I8SMN0 ndufaf5 UniProt A0A6I8SMN0 37 EQUAL 345 EQUAL Reactome DB_ID: 10503534 1 UniProt:A0A6I8SRG6 UniProt A0A6I8SRG6 45 EQUAL 333 EQUAL Reactome DB_ID: 10437993 1 UniProt:Q5G7J0 nd1 UniProt Q5G7J0 1 EQUAL 318 EQUAL Reactome DB_ID: 10503536 1 315kDa subcomplex [mitochondrial inner membrane] 315kDa subcomplex Reactome DB_ID: 10503526 1 Reactome DB_ID: 10503530 1 37 EQUAL 345 EQUAL Reactome DB_ID: 10503534 1 45 EQUAL 333 EQUAL Reactome DB_ID: 10437993 1 1 EQUAL 318 EQUAL Reactome Database ID Release 81 10503536 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503536 Reactome R-XTR-6799189 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-XTR-6799189.1 Reactome Database ID Release 81 10503576 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503576 Reactome R-XTR-6799191 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-XTR-6799191.1 A complex I intermediate of 315kDa (reestimated from the original 400kDa) is formed centred around the core subunits NADH dehydrogenase [ubiquinone] iron-sulfur proteins 2 and 3 (NDUFS2 and NDUFS3) with other complex I subunits and assembly factor subunits (forming IP and HP subcomplexes). The IP subcomplex is anchored to the inner mitochondrial membrane by NADH-ubiquinone oxidoreductase chain 1 (MT-ND1) (together with NDUFAF5 and/or 6) (Mckenzie & Ryan 2010, Andrews et al. 2013). inferred by electronic annotation IEA GO IEA COA1:MT-ND2, TMEM186:MT-ND3, MT-ND6, NDUFB6 bind the MCIA complex to form a 370kDa subcomplex COA1:MT-ND2, TMEM186:MT-ND3, MT-ND6, NDUFB6 bind the MCIA complex to form a 370kDa subcomplex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10437967 1 UniProt:Q28HL5 ndufb6 UniProt Q28HL5 2 EQUAL 128 EQUAL Reactome DB_ID: 10437963 1 UniProt:Q5G7H9 nd6 UniProt Q5G7H9 1 EQUAL 174 EQUAL Reactome DB_ID: 10503562 1 MCIA complex [mitochondrial inner membrane] MCIA complex Reactome DB_ID: 10503544 1 UniProt:Q0V9C9 ecsit UniProt Q0V9C9 49 EQUAL 431 EQUAL Reactome DB_ID: 10503540 1 UniProt:A0A803JIV0 acad9 UniProt A0A803JIV0 1 EQUAL 621 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10503560 1 Homologues of TMEM126B [mitochondrial inner membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity tmem126a [mitochondrial inner membrane] TMEM126B [mitochondrial inner membrane] TMEM126B [mitochondrial inner membrane] UniProt A0A803KIF1 UniProt A0A803K978 UniProt A0A7D9NMF8 Reactome DB_ID: 10503546 1 Ghost homologue of NDUFAF1 [mitochondrial inner membrane] Ghost homologue of NDUFAF1 Reactome Database ID Release 81 10503562 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503562 Reactome R-XTR-5689052 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-XTR-5689052.1 Reactome DB_ID: 10437977 1 COA1:MT-ND2 [mitochondrial inner membrane] COA1:MT-ND2 Reactome DB_ID: 10437975 1 UniProt:F6YDW6 coa1 UniProt F6YDW6 1 EQUAL 146 EQUAL Reactome DB_ID: 10437971 1 UniProt:Q5G7I9 nd2 UniProt Q5G7I9 1 EQUAL 347 EQUAL Reactome Database ID Release 81 10437977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437977 Reactome R-XTR-9708004 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-XTR-9708004.1 Reactome DB_ID: 10437987 1 TMEM186:MT-ND3 [mitochondrial inner membrane] TMEM186:MT-ND3 Reactome DB_ID: 10437981 1 UniProt:Q5G7I3 nd3 UniProt Q5G7I3 1 EQUAL 115 EQUAL Reactome DB_ID: 10437985 1 UniProt:A0A6I8QWJ0 tmem186 UniProt A0A6I8QWJ0 1 EQUAL 213 EQUAL Reactome Database ID Release 81 10437987 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437987 Reactome R-XTR-9708002 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-XTR-9708002.1 Reactome DB_ID: 10503564 1 370 kDa subcomplex [mitochondrial inner membrane] 370 kDa subcomplex Reactome DB_ID: 10437967 1 2 EQUAL 128 EQUAL Reactome DB_ID: 10437963 1 1 EQUAL 174 EQUAL Reactome DB_ID: 10503562 1 Reactome DB_ID: 10437977 1 Reactome DB_ID: 10437987 1 Reactome Database ID Release 81 10503564 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503564 Reactome R-XTR-6799190 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-XTR-6799190.1 Reactome Database ID Release 81 10503584 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503584 Reactome R-XTR-6799199 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-XTR-6799199.1 Membrane arm subunits COA1:MT-ND2, TMEM186:MT-ND3, MT-ND6 and NDUFB6 associate with the assembly factors TMEM126B, NDUFAF1, ECSIT and ACAD9 (which form the MCIA complex) forming a 370kDa subcomplex (Mckenzie & Ryan 2010, Andrews et al. 2013). Formosa et al. identified TMEM186 and COA1 as components of the MCIA complex with loss of either resulting in MCIA complex defects and reduced complex I assembly (Formosa et al. 2020). Transmembrane protein 186 (TMEM186) interacts strongly with ND3 while cytochrome c oxidase assembly factor 1 homolog (COA1) interacts with ND2. 32320651 Pubmed 2020 Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly Complex Factors in the Biogenesis of Complex I Formosa, Luke E Muellner-Wong, Linden Reljic, Boris Sharpe, Alice J Jackson, Thomas D Beilharz, Traude H Stojanovski, Diana Lazarou, Michael Stroud, David A Ryan, Michael T Cell Rep 31:107541 inferred by electronic annotation IEA GO IEA The 315kDa subcomplex binds the 370kDa subcomplex to form the 550kDa complex The 315kDa subcomplex binds the 370kDa subcomplex to form the 550kDa complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10503564 1 Reactome DB_ID: 10503536 1 Reactome DB_ID: 10503566 1 550kDa complex [mitochondrial inner membrane] 550kDa complex Reactome DB_ID: 10503564 1 Reactome DB_ID: 10503536 1 Reactome Database ID Release 81 10503566 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503566 Reactome R-XTR-6799176 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-XTR-6799176.1 Reactome Database ID Release 81 10503586 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503586 Reactome R-XTR-6799202 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-XTR-6799202.1 The 315kDa and 370kDa subcomplexes associate to form a 550kDa complex (Mckenzie & Ryan 2010, Andrews et al. 2013). inferred by electronic annotation IEA GO IEA ND4, ND5 bind the 550kDa complex to form the 815kDa complex ND4, ND5 bind the 550kDa complex to form the 815kDa complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10503566 1 Reactome DB_ID: 10437955 1 UniProt:Q5G7I1 nd4 UniProt Q5G7I1 1 EQUAL 459 EQUAL Reactome DB_ID: 10437959 1 UniProt:Q5G7I0 nd5 UniProt Q5G7I0 1 EQUAL 603 EQUAL Reactome DB_ID: 10503568 1 815kDa complex [mitochondrial inner membrane] 815kDa complex Reactome DB_ID: 10503566 1 Reactome DB_ID: 10437955 1 1 EQUAL 459 EQUAL Reactome DB_ID: 10437959 1 1 EQUAL 603 EQUAL Reactome Database ID Release 81 10503568 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503568 Reactome R-XTR-6799187 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-XTR-6799187.1 Reactome Database ID Release 81 10503582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503582 Reactome R-XTR-6799197 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-XTR-6799197.1 Distal components of the membrane arm MT-ND4 and 5 associate with the 550kDa complex to form the 815kDa complex (Mckenzie & Ryan 2010, Andrews et al. 2013). inferred by electronic annotation IEA GO IEA The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex, resulting in Complex I The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex, resulting in Complex I This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 10503578 1 980kDa complex [mitochondrial inner membrane] 980kDa complex Reactome DB_ID: 10437951 1 Ghost homologue of NDUFS5 [mitochondrial inner membrane] Ghost homologue of NDUFS5 Reactome DB_ID: 10503574 1 FP subcomplex [mitochondrial inner membrane] FP subcomplex Reactome DB_ID: 10437941 1 Reactome DB_ID: 10503572 1 UniProt:F7BZZ2 ndufaf2 UniProt F7BZZ2 1 EQUAL 169 EQUAL Reactome DB_ID: 10437923 1 Ghost homologue of NDUFA12 [mitochondrial inner membrane] Ghost homologue of NDUFA12 Reactome DB_ID: 10437947 1 Reactome DB_ID: 10437935 1 NDUFS1:2x4Fe-4S [mitochondrial matrix] NDUFS1:2x4Fe-4S Reactome DB_ID: 169274 2 Reactome DB_ID: 10437933 1 Ghost homologue of NDUFS1 [mitochondrial matrix] Ghost homologue of NDUFS1 Reactome Database ID Release 81 10437935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437935 Reactome R-XTR-164297 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-XTR-164297.1 Reactome DB_ID: 10437931 1 UniProt:F6ZWK3 mfsd4b UniProt F6ZWK3 29 EQUAL 124 EQUAL Reactome DB_ID: 10437921 1 UniProt:A0A803JD50 ndufv3 UniProt A0A803JD50 35 EQUAL 108 EQUAL Reactome DB_ID: 10437927 1 UniProt:A0A6I8PQR2 ndufs4 UniProt A0A6I8PQR2 43 EQUAL 175 EQUAL Reactome Database ID Release 81 10503574 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503574 Reactome R-XTR-5689686 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-XTR-5689686.1 Reactome DB_ID: 10503568 1 Reactome Database ID Release 81 10503578 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503578 Reactome R-XTR-6799183 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-XTR-6799183.1 Reactome DB_ID: 10503572 1 1 EQUAL 169 EQUAL Reactome DB_ID: 10503506 1 47 EQUAL 441 EQUAL Reactome DB_ID: 10503518 1 1 EQUAL 175 EQUAL Reactome DB_ID: 10503514 1 1 EQUAL 184 EQUAL Reactome DB_ID: 10503562 1 Reactome DB_ID: 10438117 1 Complex I [mitochondrial inner membrane] Complex I Reactome DB_ID: 10437951 1 Reactome DB_ID: 10438115 1 815kDa complex (-MCIA, NDUFAF3,4,5,6,7,TIMMDC1) [mitochondrial inner membrane] 815kDa complex (-MCIA, NDUFAF3,4,5,6,7,TIMMDC1) Reactome DB_ID: 10438113 1 550kDa complex (-MCIA, NDUFAF3,4,5,6,7,TIMMDC1) [mitochondrial inner membrane] 550kDa complex (-MCIA, NDUFAF3,4,5,6,7,TIMMDC1) Reactome DB_ID: 10437989 1 370 kDa subcomplex (-MCIA complex) [mitochondrial inner membrane] 370 kDa subcomplex (-MCIA complex) Reactome DB_ID: 10437967 1 2 EQUAL 128 EQUAL Reactome DB_ID: 10437963 1 1 EQUAL 174 EQUAL Reactome DB_ID: 10437977 1 Reactome DB_ID: 10437987 1 Reactome Database ID Release 81 10437989 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437989 Reactome R-XTR-6799177 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-XTR-6799177.1 Reactome DB_ID: 10438111 1 315kDa subcomplex (-NDUFAF3,4,5,6,7,TIMMDC1) [mitochondrial inner membrane] 315kDa subcomplex (-NDUFAF3,4,5,6,7,TIMMDC1) Reactome DB_ID: 10438109 1 Intermediate 2 (-NDUFAF3,4,7,TIMMDC1) [mitochondrial inner membrane] Intermediate 2 (-NDUFAF3,4,7,TIMMDC1) Reactome DB_ID: 10438077 1 Reactome DB_ID: 10438107 1 Intermediate 1 (-NDUFAF3,4,7, TIMMDC1) [mitochondrial inner membrane] Intermediate 1 (-NDUFAF3,4,7, TIMMDC1) Reactome DB_ID: 10438099 1 Reactome DB_ID: 10438105 1 Reactome DB_ID: 10438083 1 Reactome DB_ID: 10438093 1 37 EQUAL 264 EQUAL Reactome DB_ID: 10438089 1 Reactome Database ID Release 81 10438107 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438107 Reactome R-XTR-6801264 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-XTR-6801264.1 Reactome Database ID Release 81 10438109 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438109 Reactome R-XTR-6801262 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-XTR-6801262.1 Reactome DB_ID: 10437993 1 1 EQUAL 318 EQUAL Reactome Database ID Release 81 10438111 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438111 Reactome R-XTR-6801267 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-XTR-6801267.1 Reactome Database ID Release 81 10438113 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438113 Reactome R-XTR-6801265 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-XTR-6801265.1 Reactome DB_ID: 10437955 1 1 EQUAL 459 EQUAL Reactome DB_ID: 10437959 1 1 EQUAL 603 EQUAL Reactome Database ID Release 81 10438115 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438115 Reactome R-XTR-6799194 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-XTR-6799194.1 Reactome DB_ID: 10437949 1 FP subcomplex (-NDUFAF2) [mitochondrial inner membrane] FP subcomplex (-NDUFAF2) Reactome DB_ID: 10437941 1 Reactome DB_ID: 10437923 1 Reactome DB_ID: 10437947 1 Reactome DB_ID: 10437935 1 Reactome DB_ID: 10437931 1 29 EQUAL 124 EQUAL Reactome DB_ID: 10437921 1 35 EQUAL 108 EQUAL Reactome DB_ID: 10437927 1 43 EQUAL 175 EQUAL Reactome Database ID Release 81 10437949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437949 Reactome R-XTR-6799184 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-XTR-6799184.1 Reactome Database ID Release 81 10438117 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438117 Reactome R-XTR-6799192 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-XTR-6799192.1 Reactome DB_ID: 10503530 1 37 EQUAL 345 EQUAL Reactome DB_ID: 10503534 1 45 EQUAL 333 EQUAL Reactome DB_ID: 10503522 1 1 EQUAL 285 EQUAL Reactome Database ID Release 81 10503580 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503580 Reactome R-XTR-6799196 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-XTR-6799196.1 In the last step, the MCIA complex and it is assumed all of the assembly factors (NDUFAF2-7, TIMMDC1) dissociate from the 980kDa complex to leave mature Complex I (Mckenzie & Ryan 2010, Andrews et al. 2013). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 81 10524942 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10524942 Reactome R-XTR-6799198 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-XTR-6799198.1 GO 0032981 GO biological process Complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) utilises NADH formed from glycolysis and the TCA cycle to pump protons out of the mitochondrial matrix. It is the largest enzyme complex in the electron transport chain, containing 45 subunits. Seven subunits (ND1-6, ND4L) are encoded by mitochondrial DNA, the remainder encoded in the nucleus. The enzyme has a FMN prosthetic group and 8 Iron-Sulfur (Fe-S) clusters. The subunits are assembled together in a coordinated manner via preassembled subcomplexes to form the mature holoenzyme. The so-called "assembly factor" proteins, acting intrinsically or transiently, are required for constructing complex I although their exact roles in the biogenesis are not fully understood (Fernandez-Vizarra et al. 2009, Mckenzie & Ryan 2010, Mimaki et al. 2012, Andrews et al. 2013). 16760263 Pubmed 2006 Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process Fontanesi, Flavia Soto, Ileana C Horn, Darryl Barrientos, Antoni Am. J. Physiol., Cell Physiol. 291:C1129-47 inferred by electronic annotation IEA GO IEA 7.1.1.2 Complex I oxidises NADH to NAD+, reduces CoQ to QH2 Complex I oxidises NADH to NAD+, reduces CoQ to QH2 NADH enters the respiratory chain at Complex I This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 73663 1 coenzyme Q10 [ChEBI:46245] coenzyme Q10 ChEBI 46245 Reactome DB_ID: 113529 5 Reactome DB_ID: 29362 1 Reactome DB_ID: 163953 4 Reactome DB_ID: 76633 1 ubiquinol [ChEBI:17976] ubiquinol QH2 CoQH2 Coenzyme QH2 ChEBI 17976 Reactome DB_ID: 113526 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10438117 GO 0008137 GO molecular function Reactome Database ID Release 81 10438118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438118 Reactome Database ID Release 81 10438124 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438124 Reactome R-XTR-163217 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-XTR-163217.1 GO 0006120 GO biological process Complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) utilizes NADH formed from glycolysis and the TCA cycle to pump protons out of the mitochondrial matrix. It is the largest enzyme complex in the electron transport chain, containing 45 subunits. Seven subunits (ND1-6, ND4L) are encoded by mitochondrial DNA (Loeffen et al [1998]), the remainder are encoded in the nucleus. The enzyme has a FMN prosthetic group and 8 Iron-Sulfur (Fe-S) clusters. The electrons from NADH oxidation pass through the flavin (FMN) and Fe-S clusters to ubiquinone (CoQ). This electron transfer is coupled with the translocation of protons from the mitochondrial matrix to the intermembrane space. For each electron transferred, 2 protons can be pumped out of the matrix. As there are 2 electrons transferred, 4 protons can be pumped out.<br>Complex I is made up of 3 sub-complexes - Iron-Sulfur protein fraction (IP), Flavoprotein fraction (FP) and the Hydrophobic protein fraction (HP), probably arranged in an L-shaped structure with the IP and FP fractions protruding into the mitochondrial matrix and the HP arm lying within the inner mitochondrial membrane. The overall reaction can be summed as below:<br><b>NADH + Ubiquinone + 5H+ (mito. matrix) = NAD+ + Ubiquinol + 4H+ (intermemb. space)<br></b>The electrons from complex I are transferred to ubiquinone (Coenzyme Q, CoQ), a small mobile carrier of electrons located within the inner membrane. Ubiquinone is reduced to ubiquinol (QH2) during this process.<br><br>Mitochondrial coenzyme Q-binding protein COQ10 homologs A and B (COQ10A and B) are thought to be required for correct coenzyme CoQ in the respiratory chain. Their function in humans is unknown but the yeast model suggests functions in facilitating de novo CoQ biosynthesis and in delivering it to one or more complexes of the respiratory electron transport chain (Barros et al. 2005, Allan et al. 2013). 11695836 Pubmed 2001 Human NADH:ubiquinone oxidoreductase Smeitink, J Sengers, R Trijbels, F van den Heuvel, L J Bioenerg Biomembr 33:259-66 12837546 Pubmed 2003 The nuclear encoded subunits of complex I from bovine heart mitochondria Hirst, J Carroll, J Fearnley, IM Shannon, RJ Walker, JE Biochim Biophys Acta 1604:135-50 16230336 Pubmed 2005 The Saccharomyces cerevisiae COQ10 gene encodes a START domain protein required for function of coenzyme Q in respiration Barros, Mario H Johnson, Alisha Gin, Peter Marbois, Beth N Clarke, Catherine F Tzagoloff, Alexander J. Biol. Chem. 280:42627-35 14741580 Pubmed 2004 The gross structure of the respiratory complex I: a Lego System Friedrich, T Bottcher, B Biochim Biophys Acta 1608:1-9 23270816 Pubmed 2013 A conserved START domain coenzyme Q-binding polypeptide is required for efficient Q biosynthesis, respiratory electron transport, and antioxidant function in Saccharomyces cerevisiae Allan, Christopher M Hill, Shauna Morvaridi, Susan Saiki, Ryoichi Johnson, Jarrett S Liau, Wei-Siang Hirano, Kathleen Kawashima, Tadashi Ji, Ziming Loo, Joseph A Shepherd, Jennifer N Clarke, Catherine F Biochim. Biophys. Acta 1831:776-91 15250827 Pubmed 2004 Structural organization of mitochondrial human complex I: role of the ND4 Bourges, I Ramus, C Mousson de Camaret, B Beugnot, R Remacle, C Cardol, P Hofhaus, G Issartel, JP Biochem J 383:491-9 9878551 Pubmed 1998 cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: Loeffen, JL Triepels, RH van den Heuvel, LP Schuelke, Markus Buskens, CA Smeets, RJ Trijbels, JM Smeitink, JA Biochem Biophys Res Commun 253:415-22 12231006 Pubmed 2002 The energy-transducing NADH: quinone oxidoreductase, complex I Yano, T Mol Aspects Med 23:345-68 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 81 10438125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438125 Reactome DB_ID: 10438122 UniProt:Q0IHX6 coq10a UniProt Q0IHX6 16 EQUAL 247 EQUAL Reducing equivalents from beta-oxidation of fatty acids transfer to ETF Reducing equivalents from beta-oxidation of fatty acids transfer to ETF This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 31649 1 Reactome DB_ID: 10439442 1 ETF:FAD [mitochondrial matrix] ETF:FAD Reactome DB_ID: 113596 1 Reactome DB_ID: 10439440 1 UniProt:Q6P7K1 etfb UniProt Q6P7K1 2 EQUAL 255 EQUAL Reactome DB_ID: 10439436 1 UniProt:A0A6I8RM83 etfa UniProt A0A6I8RM83 Reactome DB_ID: 159448 1 adenosine 5'-monophosphate(2-) [ChEBI:456215] adenosine 5'-monophosphate(2-) Adenosine-5-monophosphate(2-) AMP 5'-O-phosphonatoadenosine AMP dianion AMP(2-) Adenosine-5-monophosphate dianion ChEBI 456215 Reactome Database ID Release 81 10439442 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439442 Reactome R-XTR-169267 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-XTR-169267.1 Reactome DB_ID: 113596 1 Reactome DB_ID: 10439444 1 ETF:FADH2 [mitochondrial matrix] ETF:FADH2 Reactome DB_ID: 31649 1 Reactome DB_ID: 10439440 1 2 EQUAL 255 EQUAL Reactome DB_ID: 10439436 1 Reactome DB_ID: 159448 1 Reactome Database ID Release 81 10439444 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439444 Reactome R-XTR-169268 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-XTR-169268.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10439442 GO 0009055 GO molecular function Reactome Database ID Release 81 10439445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439445 Reactome Database ID Release 81 10439447 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439447 Reactome R-XTR-169260 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-XTR-169260.1 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reducing equivalents from the beta-oxidation of fatty acyl CoAs are transferred to ETF, reducing the ETF-bound FAD to FADH2 (Wood 1999). 10327278 Pubmed 1999 Defects in mitochondrial beta-oxidation of fatty acids Wood, P A Curr. Opin. Lipidol. 10:107-12 inferred by electronic annotation IEA GO IEA 1.5.5.1 ETFDH oxidises ETF (reduced) to ETF, reduces CoQ to QH2 ETFDH oxidises ETF (reduced) to ETF, reduces CoQ to QH2 Transfer of electrons from ETF to ubiquinone by ETF-QO This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 73663 1 Reactome DB_ID: 10439444 1 Reactome DB_ID: 76633 1 Reactome DB_ID: 10439442 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10439451 UniProt:Q6GL88 etfdh UniProt Q6GL88 34 EQUAL 617 EQUAL GO 0004174 GO molecular function Reactome Database ID Release 81 10439452 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439452 Reactome Database ID Release 81 10439454 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10439454 Reactome R-XTR-169270 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-XTR-169270.1 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2) (Estornell et al. 1992, MacLennan et al. 1997). 1327877 Pubmed 1992 Saturation kinetics of coenzyme Q in NADH and succinate oxidation in beef heart mitochondria Estornell, E Fato, R Castelluccio, C Cavazzoni, M Parenti Castelli, G Lenaz, G FEBS Lett. 311:107-9 4288886 Pubmed 1966 Studies on the mechanims of oxidative phosphorylation. IX. Effect of cytochrome c on energy-linked processes MacLennan, D H Lenaz, G Szarkowska, L J. Biol. Chem. 241:5251-9 inferred by electronic annotation IEA GO IEA 7.1.1.9 Electron transfer from reduced cytochrome c to molecular oxygen Electron transfer from reduced cytochrome c to molecular oxygen This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome DB_ID: 113533 1 dioxygen [ChEBI:15379] dioxygen ChEBI 15379 Reactome DB_ID: 113529 12 Reactome DB_ID: 10437802 4 Cytochrome c (reduced) [mitochondrial inner membrane] Cytochrome c (reduced) Reactome DB_ID: 3341317 1 ferroheme [ChEBI:38573] ferroheme ferrohaem ChEBI 38573 Converted from EntitySet in Reactome Reactome DB_ID: 10437800 1 Homologues of CYCS [mitochondrial inner membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity cyct [mitochondrial inner membrane] cyct [mitochondrial inner membrane] UniProt F6T0D5 UniProt Q6PBF4 Reactome Database ID Release 81 10437802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437802 Reactome R-XTR-352609 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-XTR-352609.1 Reactome DB_ID: 10437804 4 Cytochrome c (oxidised) [mitochondrial inner membrane] Cytochrome c (oxidised) Reactome DB_ID: 3341371 1 ferriheme [ChEBI:38574] ferriheme ferrihaem ChEBI 38574 Converted from EntitySet in Reactome Reactome DB_ID: 10437800 1 Reactome Database ID Release 81 10437804 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437804 Reactome R-XTR-352607 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-XTR-352607.1 Reactome DB_ID: 113521 2 Reactome DB_ID: 163953 8 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10437858 Cytochrome c oxidase [mitochondrial inner membrane] Cytochrome c oxidase