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 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 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 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> LEFT-TO-RIGHT 1.1.1.40 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> MAL (S)-Malate (S)-malic acid L-Malate L-Apple acid L-Malic acid L-2-Hydroxybutanedioic acid Reactome DB_ID: 198498 cytosol GENE ONTOLOGY GO:0005829 (S)-malate(2-) [ChEBI:15589] (S)-malate(2-) (S)-malate ChEBI CHEBI:15589 Reactome Database ID Release 81 198498 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198498 Reactome R-ALL-198498 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-198498.4 Reactome http://www.reactome.org COMPOUND C00149 additional information MI MI:0361 TPN NADP+ NADP NADP(+) Nicotinamide adenine dinucleotide phosphate beta-Nicotinamide adenine dinucleotide phosphate Triphosphopyridine nucleotide NADP(3-) Reactome DB_ID: 29366 NADP(3-) [ChEBI:58349] NADP(3-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP(+) NADP trianion ChEBI CHEBI:58349 Reactome Database ID Release 81 29366 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29366 Reactome R-ALL-29366 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29366.4 COMPOUND C00006 PYR Pyruvate pyruvic acid 2-Oxopropanoate 2-Oxopropanoic acid Pyroracemic acid Reactome DB_ID: 29398 pyruvate [ChEBI:15361] pyruvate 2-oxopropanoate 2-oxopropanoic acid, ion(1-) ChEBI CHEBI:15361 Reactome Database ID Release 81 29398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29398 Reactome R-ALL-29398 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29398.4 COMPOUND C00022 H+ proton hydron Reactome DB_ID: 70106 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 81 70106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70106 Reactome R-ALL-70106 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-70106.4 COMPOUND C00080 CO2 carbon dioxide Reactome DB_ID: 113528 carbon dioxide [ChEBI:16526] carbon dioxide ChEBI CHEBI:16526 Reactome Database ID Release 81 113528 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113528 Reactome R-ALL-113528 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113528.3 COMPOUND C00011 TPNH NADPH Reactome DB_ID: 29364 NADPH(4-) [ChEBI:57783] NADPH(4-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH NADPH tetraanion ChEBI CHEBI:57783 Reactome Database ID Release 81 29364 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29364 Reactome R-ALL-29364 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29364.3 COMPOUND C00005 ACTIVATION ME1:Mg2+ tetramer Reactome DB_ID: 10517035 ME1:Mg2+ dimer Reactome DB_ID: 10517033 ME1:Mg2+ Reactome DB_ID: 10517031 Mg2+ Magnesium magnesium(2+) Mg++ Reactome DB_ID: 29926 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI CHEBI:18420 Reactome Database ID Release 81 29926 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29926 Reactome R-ALL-29926 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29926.5 COMPOUND C00305 1 me1 ME1 A0A6I8S9Q0 Reactome DB_ID: 10517029 UniProt:A0A6I8S9Q0 me1 Xenopus tropicalis NCBI Taxonomy 8364 UniProt A0A6I8S9Q0 1 EQUAL 572 EQUAL Reactome Database ID Release 81 10517029 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517029 Reactome R-XTR-400119 1 Reactome stable identifier. Use this 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-400119.1 1 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 2 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 2 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 GENE ONTOLOGY GO:0004473 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity 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 from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT 1.1.1.27 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> NADH Reactome DB_ID: 73473 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 CHEBI:57945 Reactome Database ID Release 81 73473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73473 Reactome R-ALL-73473 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-73473.4 COMPOUND C00004 NAD NAD+ NAD(+) Nicotinamide adenine dinucleotide DPN Diphosphopyridine nucleotide Reactome DB_ID: 29360 NAD(1-) [ChEBI:57540] NAD(1-) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD(+) NAD anion ChEBI CHEBI:57540 Reactome Database ID Release 81 29360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29360 Reactome R-ALL-29360 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29360.5 COMPOUND C00003 LACT (S)-Lactate (S)-lactic acid L-Lactate L-Lactic acid Reactome DB_ID: 29708 (S)-lactic acid [ChEBI:422] (S)-lactic acid ChEBI CHEBI:422 Reactome Database ID Release 81 29708 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29708 Reactome R-ALL-29708 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29708.3 COMPOUND C00186 ACTIVATION Converted from EntitySet in Reactome LDH tetramer lactate dehydrogenase complex Reactome DB_ID: 10429590 lactate dehydrogenase A2B2 complex Reactome DB_ID: 10429580 ldha LDHA Q6P7L5 Reactome DB_ID: 10429574 UniProt:Q6P7L5 ldha UniProt Q6P7L5 2 EQUAL 332 EQUAL Reactome Database ID Release 81 10429574 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429574 Reactome R-XTR-70502 1 Reactome stable identifier. Use this 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-70502.1 2 ldhb LDHB A0A803KJA8 Reactome DB_ID: 10429578 UniProt:A0A803KJA8 ldhb UniProt A0A803KJA8 2 EQUAL 334 EQUAL Reactome Database ID Release 81 10429578 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429578 Reactome R-XTR-70503 1 Reactome stable identifier. Use this 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-70503.1 2 Reactome Database ID Release 81 10429580 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429580 Reactome R-XTR-70513 1 Reactome stable identifier. Use this 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-70513.1 lactate dehydrogenase A3B complex Reactome DB_ID: 10429582 3 1 Reactome Database ID Release 81 10429582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429582 Reactome R-XTR-70504 1 Reactome stable identifier. Use this 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-70504.1 lactate dehydrogenase A4 complex Reactome DB_ID: 10429584 4 Reactome Database ID Release 81 10429584 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429584 Reactome R-XTR-70508 1 Reactome stable identifier. Use this 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-70508.1 lactate dehydrogenase AB3 complex Reactome DB_ID: 10429586 1 3 Reactome Database ID Release 81 10429586 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429586 Reactome R-XTR-70506 1 Reactome stable identifier. Use this 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-70506.1 LDHB tetramer Reactome DB_ID: 10429588 4 Reactome Database ID Release 81 10429588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429588 Reactome R-XTR-70516 1 Reactome stable identifier. Use this 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-70516.1 Reactome Database ID Release 81 10429590 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429590 Reactome R-XTR-184549 1 Reactome stable identifier. Use this 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-184549.1 GENE ONTOLOGY GO:0004459 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 LEFT-TO-RIGHT 1.1.1.27 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> H+ hydron Reactome DB_ID: 113529 mitochondrial matrix GENE ONTOLOGY GO:0005759 Reactome Database ID Release 81 113529 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113529 Reactome R-ALL-113529 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113529.4 COMPOUND C00080 PYR Pyruvate pyruvic acid 2-Oxopropanoate 2-Oxopropanoic acid Pyroracemic acid Reactome DB_ID: 113557 Reactome Database ID Release 81 113557 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113557 Reactome R-ALL-113557 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113557.4 COMPOUND C00022 NADH Reactome DB_ID: 29362 Reactome Database ID Release 81 29362 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29362 Reactome R-ALL-29362 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29362.3 COMPOUND C00004 LACT (S)-Lactate (S)-lactic acid L-Lactate L-Lactic acid Reactome DB_ID: 6807616 Reactome Database ID Release 81 6807616 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6807616 Reactome R-ALL-6807616 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6807616.3 COMPOUND C00186 NAD NAD+ NAD(+) Nicotinamide adenine dinucleotide DPN Diphosphopyridine nucleotide NAD+ Reactome DB_ID: 113526 Reactome Database ID Release 81 113526 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113526 Reactome R-ALL-113526 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113526.5 COMPOUND C00003 ACTIVATION ldha LDHAL6B Q6P7L5 Reactome DB_ID: 10505656 1 EQUAL 381 EQUAL Reactome Database ID Release 81 10505656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10505656 Reactome R-XTR-6807613 1 Reactome stable identifier. Use this 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-6807613.1 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 LEFT-TO-RIGHT 1.1.1.27 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> ACTIVATION 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). LEFT-TO-RIGHT 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> PYR Pyruvate pyruvic acid 2-Oxopropanoate 2-Oxopropanoic acid Pyroracemic acid Reactome DB_ID: 9012375 mitochondrial intermembrane space GENE ONTOLOGY GO:0005758 Reactome Database ID Release 81 9012375 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9012375 Reactome R-ALL-9012375 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9012375.4 COMPOUND C00022 ACTIVATION vdac1 VDAC1 Q28HL9 Reactome DB_ID: 10487873 mitochondrial outer membrane GENE ONTOLOGY GO:0005741 UniProt:Q28HL9 vdac1 UniProt Q28HL9 2 EQUAL 283 EQUAL Reactome Database ID Release 81 10487873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10487873 Reactome R-XTR-1267988 1 Reactome stable identifier. Use this 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-1267988.1 GENE ONTOLOGY GO:0008308 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 LEFT-TO-RIGHT 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> CoA CoA-SH coenzyme A Reactome DB_ID: 29374 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} CoA ChEBI CHEBI:57287 Reactome Database ID Release 81 29374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29374 Reactome R-ALL-29374 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29374.4 COMPOUND C00010 CO2 carbon dioxide Reactome DB_ID: 29376 Reactome Database ID Release 81 29376 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29376 Reactome R-ALL-29376 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29376.3 COMPOUND C00011 Ac-CoA Acetyl coenzyme A acetyl-CoA Reactome DB_ID: 113559 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) acetyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-coenzyme A(4-) acetyl-CoA tetraanion AcCoA(4-) ChEBI CHEBI:57288 Reactome Database ID Release 81 113559 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113559 Reactome R-ALL-113559 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113559.4 COMPOUND C00024 ACTIVATION lipo-PDH Reactome DB_ID: 10430309 lipo-K-132,K259-DLAT trimer Reactome DB_ID: 10430303 dlat lipo-K132,K259-DLAT F6Z0R6 Reactome DB_ID: 10430301 UniProt:F6Z0R6 dlat UniProt F6Z0R6 132 EQUAL N6-lipoyl-L-lysine MOD MOD:00127 259 EQUAL 87 EQUAL 647 EQUAL Reactome Database ID Release 81 10430301 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430301 Reactome R-XTR-69969 1 Reactome stable identifier. Use this 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-69969.1 3 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 20 pdhx PDHX A0A6I8RWC7 Reactome DB_ID: 10430307 UniProt:A0A6I8RWC7 pdhx UniProt A0A6I8RWC7 54 EQUAL 501 EQUAL Reactome Database ID Release 81 10430307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430307 Reactome R-XTR-70059 1 Reactome stable identifier. Use this 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-70059.1 12 PDH E1 Reactome DB_ID: 10430295 pdhb PDHB Q5BKI5 Reactome DB_ID: 10430287 UniProt:Q5BKI5 pdhb UniProt Q5BKI5 31 EQUAL 359 EQUAL Reactome Database ID Release 81 10430287 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430287 Reactome R-XTR-69967 1 Reactome stable identifier. Use this 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-69967.1 2 pdha1 PDHA1 A0A803KHT8 Reactome DB_ID: 10430291 UniProt:A0A803KHT8 pdha1 UniProt A0A803KHT8 31 EQUAL 390 EQUAL Reactome Database ID Release 81 10430291 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430291 Reactome R-XTR-69966 1 Reactome stable identifier. Use this 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-69966.1 2 TDP Thiamin diphosphate thiamine(1+) diphosphate chloride Thiamine diphosphate Thiamin pyrophosphate TPP ThPP Reactome DB_ID: 113547 thiamine(1+) diphosphate(3-) [ChEBI:58937] thiamine(1+) diphosphate(3-) thiamine diphosphate dianion thiamine diphosphate thiamine diphosphate(2-) ChEBI CHEBI:58937 Reactome Database ID Release 81 113547 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113547 Reactome R-ALL-113547 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113547.4 COMPOUND C00068 2 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 22 aKADH E3 dimer Reactome DB_ID: 10429770 aKADH E3 Reactome DB_ID: 10429768 dld DLD A0A6I8R6Y1 Reactome DB_ID: 10429766 UniProt:A0A6I8R6Y1 dld UniProt A0A6I8R6Y1 36 EQUAL 509 EQUAL Reactome Database ID Release 81 10429766 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429766 Reactome R-XTR-69978 1 Reactome stable identifier. Use this 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-69978.1 1 FAD Flavin adenine dinucleotide FAD(3-) Reactome DB_ID: 113596 FAD(3-) [ChEBI:57692] FAD(3-) FAD trianion FAD ChEBI CHEBI:57692 Reactome Database ID Release 81 113596 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113596 Reactome R-ALL-113596 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113596.3 COMPOUND C00016 1 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 2 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 6 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 GENE ONTOLOGY GO:0004738 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 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> LEFT-TO-RIGHT 3.8.1 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> H2O water Reactome DB_ID: 113521 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 81 113521 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113521 Reactome R-ALL-113521 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113521.3 COMPOUND C00001 DCA dichloroacetic acid dichloroacetate dicholoroacetic acid Reactome DB_ID: 9010792 dichloroacetate [Guide to Pharmacology:4518] dichloroacetate dichloroacetic acid Guide to Pharmacology 4518 Reactome Database ID Release 81 9010792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9010792 Reactome R-ALL-9010792 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9010792.2 ChEBI 28240 glyoxylate glyoxylic acid Reactome DB_ID: 904849 glyoxylic acid [ChEBI:16891] glyoxylic acid ChEBI CHEBI:16891 Reactome Database ID Release 81 904849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=904849 Reactome R-ALL-904849 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-904849.4 HCl hydrochloric acid hydrogen chloride Reactome DB_ID: 3301973 hydrogen chloride [ChEBI:17883] hydrogen chloride ChEBI CHEBI:17883 Reactome Database ID Release 81 3301973 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3301973 Reactome R-ALL-3301973 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-3301973.3 2 ACTIVATION GSTZ1 dimer Reactome DB_ID: 10516940 gstz1 GSTZ1 A0A803J8A8 Reactome DB_ID: 10516938 UniProt:A0A803J8A8 gstz1 UniProt A0A803J8A8 1 EQUAL 216 EQUAL Reactome Database ID Release 81 10516938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10516938 Reactome R-XTR-9011574 1 Reactome stable identifier. Use this 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-9011574.1 2 GSH Reduced glutathione glutathione 5-L-Glutamyl-L-cysteinylglycine N-(N-gamma-L-Glutamyl-L-cysteinyl)glycine gamma-L-Glutamyl-L-cysteinyl-glycine Reactome DB_ID: 1655887 glutathione [ChEBI:16856] glutathione ChEBI CHEBI:16856 Reactome Database ID Release 81 1655887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1655887 Reactome R-ALL-1655887 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1655887.3 COMPOUND C00051 2 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 GENE ONTOLOGY GO:0019120 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 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 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 LEFT-TO-RIGHT 2.7.11.2 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> ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113593 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 81 113593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113593 Reactome R-ALL-113593 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113593.4 COMPOUND C00002 2 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113581 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 81 113581 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113581 Reactome R-ALL-113581 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113581.4 COMPOUND C00008 2 p-lipo-PDH Reactome DB_ID: 10445553 20 phosphorylated pyruvate dehydrogenase E1 complex Reactome DB_ID: 10445551 2 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 1 12 21 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 ACTIVATION Converted from EntitySet in Reactome PDK isoforms Reactome DB_ID: 10445567 pdk1 PDK1 F6QN91 Reactome DB_ID: 10445557 UniProt:F6QN91 pdk1 UniProt F6QN91 29 EQUAL 436 EQUAL Reactome Database ID Release 81 10445557 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445557 Reactome R-XTR-203944 1 Reactome stable identifier. Use this 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-203944.1 pdk3 PDK3(?-406) A9ULF7 Reactome DB_ID: 10445561 UniProt:A9ULF7 pdk3 UniProt A9ULF7 1 EQUAL 406 EQUAL Reactome Database ID Release 81 10445561 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445561 Reactome R-XTR-203940 1 Reactome stable identifier. Use this 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-203940.1 pdk4 PDK4(?-411) Q6DFQ9 Reactome DB_ID: 10445565 UniProt:Q6DFQ9 pdk4 UniProt Q6DFQ9 1 EQUAL 411 EQUAL Reactome Database ID Release 81 10445565 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445565 Reactome R-XTR-203941 1 Reactome stable identifier. Use this 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-203941.1 Reactome Database ID Release 81 10445567 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445567 Reactome R-XTR-203947 1 Reactome stable identifier. Use this 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-203947.1 GENE ONTOLOGY GO:0004740 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 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 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 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 RXRA:PPARD:atRA Reactome DB_ID: 10444227 nucleoplasm GENE ONTOLOGY GO:0005654 atRA all-trans-retinoic acid Reactome DB_ID: 5334804 all-trans-retinoic acid [ChEBI:15367] all-trans-retinoic acid ChEBI CHEBI:15367 Reactome Database ID Release 81 5334804 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5334804 Reactome R-ALL-5334804 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5334804.3 1 RXRA:PPARD Reactome DB_ID: 10444225 rxra RXRA A0A803K2Y7 Reactome DB_ID: 10442224 UniProt:A0A803K2Y7 rxra UniProt A0A803K2Y7 1 EQUAL 462 EQUAL Reactome Database ID Release 81 10442224 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10442224 Reactome R-XTR-381319 1 Reactome stable identifier. Use this 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-381319.1 1 ppard PPARD A0A6I8SH51 Reactome DB_ID: 10444223 UniProt:A0A6I8SH51 ppard UniProt A0A6I8SH51 1 EQUAL 441 EQUAL Reactome Database ID Release 81 10444223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10444223 Reactome R-XTR-446176 1 Reactome stable identifier. Use this 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-446176.1 1 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 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 LEFT-TO-RIGHT 3.1.3.43 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> 2 Pi Orthophosphate hydrogenphosphate Phosphate Reactome DB_ID: 113548 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 81 113548 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113548 Reactome R-ALL-113548 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113548.4 COMPOUND C00009 2 ACTIVATION Converted from EntitySet in Reactome PDP Reactome DB_ID: 10445797 PDP1 complex Reactome DB_ID: 10445789 pdp1 PDP1 Q0VA38 Reactome DB_ID: 10445781 UniProt:Q0VA38 pdp1 UniProt Q0VA38 72 EQUAL 537 EQUAL Reactome Database ID Release 81 10445781 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445781 Reactome R-XTR-204149 1 Reactome stable identifier. Use this 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-204149.1 1 PDPr:FAD Reactome DB_ID: 10445787 1 pdpr PDPR A0A6I8SI05 Reactome DB_ID: 10445785 UniProt:A0A6I8SI05 pdpr UniProt A0A6I8SI05 28 EQUAL 879 EQUAL Reactome Database ID Release 81 10445785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445785 Reactome R-XTR-204171 1 Reactome stable identifier. Use this 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-204171.1 1 Reactome Database ID Release 81 10445787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445787 Reactome R-XTR-210347 1 Reactome stable identifier. Use this 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-210347.1 1 Reactome Database ID Release 81 10445789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445789 Reactome R-XTR-204162 1 Reactome stable identifier. Use this 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-204162.1 PDP2 complex Reactome DB_ID: 10445795 pdp2 PDP2 F6RH54 Reactome DB_ID: 10445793 UniProt:F6RH54 pdp2 UniProt F6RH54 67 EQUAL 529 EQUAL Reactome Database ID Release 81 10445793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445793 Reactome R-XTR-204166 1 Reactome stable identifier. Use this 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-204166.1 1 1 Reactome Database ID Release 81 10445795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445795 Reactome R-XTR-204218 1 Reactome stable identifier. Use this 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-204218.1 Reactome Database ID Release 81 10445797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10445797 Reactome R-XTR-204219 1 Reactome stable identifier. Use this 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-204219.1 GENE ONTOLOGY GO:0004741 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 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 Mg2+ magnesium magnesium(2+) Mg++ Reactome DB_ID: 109496 Reactome Database ID Release 81 109496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109496 Reactome R-ALL-109496 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-109496.3 COMPOUND C00305 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 GENE ONTOLOGY GO:0010510 gene ontology term for cellular process MI MI:0359 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 LEFT-TO-RIGHT 3.1.2.6 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> (R)-S-LGSH (R)-S-lactoylglutathione Reactome DB_ID: 5694130 (R)-S-lactoylglutathione [ChEBI:15694] (R)-S-lactoylglutathione ChEBI CHEBI:15694 Reactome Database ID Release 81 5694130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5694130 Reactome R-ALL-5694130 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5694130.3 GSH Reduced glutathione glutathione 5-L-Glutamyl-L-cysteinylglycine N-(N-gamma-L-Glutamyl-L-cysteinyl)glycine gamma-L-Glutamyl-L-cysteinyl-glycine glutathionate(1-) Reactome DB_ID: 29450 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate ion glutathionate anion glutathionate glutathione ChEBI CHEBI:57925 Reactome Database ID Release 81 29450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29450 Reactome R-ALL-29450 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29450.4 COMPOUND C00051 ACTIVATION HAGH-2:2xZn2+ Reactome DB_ID: 10499631 Zn2+ Zn++ zinc(2+) Zinc ion Zn(II) Reactome DB_ID: 29426 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 81 29426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29426 Reactome R-ALL-29426 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29426.3 COMPOUND C00038 2 hagh HAGH-2 G1K3C6 Reactome DB_ID: 10499629 UniProt:G1K3C6 hagh UniProt G1K3C6 14 EQUAL 308 EQUAL Reactome Database ID Release 81 10499629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10499629 Reactome R-XTR-6783219 1 Reactome stable identifier. Use this 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-6783219.1 1 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 GENE ONTOLOGY GO:0004416 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 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 GENE ONTOLOGY GO:0006090 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 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> LEFT-TO-RIGHT 2.3.3.1 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> OAA Oxaloacetate oxaloacetic acid Oxalacetic acid 2-oxobutanedioic acid Oxosuccinic acid Reactome DB_ID: 113587 oxaloacetate(2-) [ChEBI:16452] oxaloacetate(2-) oxosuccinate oxaloacetate dianion oxobutanedioic acid, ion(2-) oxaloacetate oxobutanedioate ChEBI CHEBI:16452 Reactome Database ID Release 81 113587 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113587 Reactome R-ALL-113587 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113587.5 COMPOUND C00036 CIT Citrate citric acid 2-Hydroxy-1,2,3-propanetricarboxylic acid 2-Hydroxytricarballylic acid Reactome DB_ID: 29654 citric acid [ChEBI:30769] citric acid ChEBI CHEBI:30769 Reactome Database ID Release 81 29654 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29654 Reactome R-ALL-29654 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29654.3 COMPOUND C00158 ACTIVATION CS dimer Reactome DB_ID: 10429950 cs CS Q28DK1 Reactome DB_ID: 10429948 UniProt:Q28DK1 cs UniProt Q28DK1 28 EQUAL 466 EQUAL Reactome Database ID Release 81 10429948 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429948 Reactome R-XTR-70972 1 Reactome stable identifier. Use this 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-70972.1 2 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 GENE ONTOLOGY GO:0004108 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 LEFT-TO-RIGHT 4.2.1.3 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> ISCIT Isocitrate D-threo-isocitric acid (1R,2S)-1-Hydroxypropane-1,2,3-tricarboxylate Isocitric acid 1-Hydroxytricarballylic acid 1-Hydroxypropane-1,2,3-tricarboxylic acid D-erythro-Isocitric acid Reactome DB_ID: 29938 D-threo-isocitrate(3-) [ChEBI:15562] D-threo-isocitrate(3-) threo-Ds-isocitrate D-threo-isocitrate ChEBI CHEBI:15562 Reactome Database ID Release 81 29938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29938 Reactome R-ALL-29938 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29938.4 COMPOUND C00451 COMPOUND C00311 ACTIVATION aco2 ACO2 Q5I0B1 Reactome DB_ID: 10429941 UniProt:Q5I0B1 aco2 UniProt Q5I0B1 28 EQUAL 780 EQUAL Reactome Database ID Release 81 10429941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429941 Reactome R-XTR-70968 1 Reactome stable identifier. Use this 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-70968.1 GENE ONTOLOGY GO:0003994 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 LEFT-TO-RIGHT 4.2.1.3 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> ACTIVATION 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). LEFT-TO-RIGHT 1.1.1.41 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> 2OG 2-Oxoglutarate 2-oxoglutaric acid Oxoglutaric acid 2-Ketoglutaric acid alpha-Ketoglutaric acid 2-oxoglutarate(2-) Reactome DB_ID: 113594 2-oxoglutarate(2-) [ChEBI:16810] 2-oxoglutarate(2-) 2-ketoglutarate alpha-ketoglutarate 2-oxopentanedioic acid, ion(2-) 2-oxoglutarate ChEBI CHEBI:16810 Reactome Database ID Release 81 113594 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113594 Reactome R-ALL-113594 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113594.4 COMPOUND C00026 ACTIVATION IDH3 complex Reactome DB_ID: 10429934 idh3a IDH3A F6SJ48 Reactome DB_ID: 10429924 UniProt:F6SJ48 idh3a UniProt F6SJ48 28 EQUAL 366 EQUAL Reactome Database ID Release 81 10429924 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429924 Reactome R-XTR-70962 1 Reactome stable identifier. Use this 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-70962.1 2 idh3b IDH3B A0A6I8RCI5 Reactome DB_ID: 10429928 UniProt:A0A6I8RCI5 idh3b UniProt A0A6I8RCI5 35 EQUAL 385 EQUAL Reactome Database ID Release 81 10429928 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429928 Reactome R-XTR-70963 1 Reactome stable identifier. Use this 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-70963.1 1 idh3g IDH3G Q5BKK0 Reactome DB_ID: 10429932 UniProt:Q5BKK0 idh3g UniProt Q5BKK0 40 EQUAL 393 EQUAL Reactome Database ID Release 81 10429932 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429932 Reactome R-XTR-70964 1 Reactome stable identifier. Use this 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-70964.1 1 Mn2+ Manganese manganese(2+) Mn(II) Reactome DB_ID: 113527 manganese(2+) [ChEBI:29035] manganese(2+) Mn(2+) MANGANESE (II) ION manganese, ion (Mn2+) manganese(II) manganous ion ChEBI CHEBI:29035 Reactome Database ID Release 81 113527 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113527 Reactome R-ALL-113527 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113527.3 COMPOUND C00034 2 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 GENE ONTOLOGY GO:0004449 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 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 LEFT-TO-RIGHT 1.1.1.42 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> TPN NADP+ NADP NADP(+) Nicotinamide adenine dinucleotide phosphate beta-Nicotinamide adenine dinucleotide phosphate Triphosphopyridine nucleotide Reactome DB_ID: 113563 NADP(+) [ChEBI:18009] NADP(+) ChEBI CHEBI:18009 Reactome Database ID Release 81 113563 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113563 Reactome R-ALL-113563 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113563.4 COMPOUND C00006 TPNH NADPH Reactome DB_ID: 113600 NADPH [ChEBI:16474] NADPH TPNH ChEBI CHEBI:16474 Reactome Database ID Release 81 113600 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113600 Reactome R-ALL-113600 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113600.2 COMPOUND C00005 ACTIVATION IDH2 dimer Reactome DB_ID: 10458086 idh2 IDH2 Q6GLF0 Reactome DB_ID: 10458084 UniProt:Q6GLF0 idh2 UniProt Q6GLF0 40 EQUAL 452 EQUAL Reactome Database ID Release 81 10458084 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458084 Reactome R-XTR-450988 1 Reactome stable identifier. Use this 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-450988.1 2 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 GENE ONTOLOGY GO:0004450 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 LEFT-TO-RIGHT 1.6.1.1 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> ACTIVATION NNT dimer Reactome DB_ID: 10458075 mitochondrial inner membrane GENE ONTOLOGY GO:0005743 nnt NNT B2GUE7 Reactome DB_ID: 10458073 UniProt:B2GUE7 nnt UniProt B2GUE7 44 EQUAL 1086 EQUAL Reactome Database ID Release 81 10458073 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10458073 Reactome R-XTR-450979 1 Reactome stable identifier. Use this 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-450979.1 2 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 GENE ONTOLOGY GO:0008746 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 LEFT-TO-RIGHT 1.2.1.105 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> SUCC-CoA Succinyl coenzyme A succinyl-CoA(5-) Reactome DB_ID: 70958 succinyl-CoA(5-) [ChEBI:57292] succinyl-CoA(5-) S-(3-carboxy-propionyl)-CoA(5-) succinyl-coenzyme A(5-) 3'-phosphonatoadenosine 5'-{3-[(3R)-4-{[3-({2-[(3-carboxylatopropanoyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}-3-hydroxy-2,2-dimethyl-4-oxobutyl]diphosphate} succinyl-CoA S-(hydrogen succinyl)CoA(5-) succinyl-CoA pentaanion ChEBI CHEBI:57292 Reactome Database ID Release 81 70958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70958 Reactome R-ALL-70958 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-70958.4 ACTIVATION lipo-aKGDH Reactome DB_ID: 10430070 lipo-aKGDH E2 Reactome DB_ID: 10430068 LIPAM lipoamide Reactome DB_ID: 29824 lipoamide [ChEBI:17460] lipoamide ChEBI CHEBI:17460 Reactome Database ID Release 81 29824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29824 Reactome R-ALL-29824 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29824.3 COMPOUND C00248 1 dlst Lipo-K110-DLST A0A803KLQ9 Reactome DB_ID: 10430066 UniProt:A0A803KLQ9 dlst UniProt A0A803KLQ9 110 EQUAL 68 EQUAL 453 EQUAL Reactome Database ID Release 81 10430066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430066 Reactome R-XTR-69993 1 Reactome stable identifier. Use this 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-69993.1 1 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 24 aKGDH E1 dimer Reactome DB_ID: 10430061 alpha-ketoglutarate dehydrogenase E1 holoenzyme Reactome DB_ID: 10430059 ogdh OGDH A0A6I8QA02 Reactome DB_ID: 10430057 UniProt:A0A6I8QA02 ogdh UniProt A0A6I8QA02 41 EQUAL 1023 EQUAL Reactome Database ID Release 81 10430057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430057 Reactome R-XTR-69981 1 Reactome stable identifier. Use this 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-69981.1 1 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 2 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 12 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 GENE ONTOLOGY GO:0034602 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 LEFT-TO-RIGHT 6.2.1.4 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> GDP Guanosine 5'-diphosphate Guanosine diphosphate GDP(3-) Reactome DB_ID: 113525 GDP(3-) [ChEBI:58189] GDP(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate(3-) GDP guanosine 5'-diphosphate trianion guanosine 5'-diphosphate GDP trianion ChEBI CHEBI:58189 Reactome Database ID Release 81 113525 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113525 Reactome R-ALL-113525 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113525.3 COMPOUND C00035 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 113573 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 81 113573 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113573 Reactome R-ALL-113573 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113573.3 COMPOUND C00044 SUCCA Succinate succinic acid Butanedionic acid Ethylenesuccinic acid succinate(2-) Reactome DB_ID: 113536 succinate(2-) [ChEBI:30031] succinate(2-) (-)OOC-CH2-CH2-COO(-) succinate butanedioic acid, ion(2-) butanedioate ChEBI CHEBI:30031 Reactome Database ID Release 81 113536 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113536 Reactome R-ALL-113536 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113536.4 COMPOUND C00042 ACTIVATION SUCLG1:SUCLG2 Reactome DB_ID: 10430603 suclg1 SUCLG1 A0A6I8S5E0 Reactome DB_ID: 10430000 UniProt:A0A6I8S5E0 suclg1 UniProt A0A6I8S5E0 41 EQUAL 346 EQUAL Reactome Database ID Release 81 10430000 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430000 Reactome R-XTR-156623 1 Reactome stable identifier. Use this 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-156623.1 1 suclg2 SUCLG2 A0A1B8YAJ2 Reactome DB_ID: 10430601 UniProt:A0A1B8YAJ2 suclg2 UniProt A0A1B8YAJ2 38 EQUAL 432 EQUAL Reactome Database ID Release 81 10430601 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430601 Reactome R-XTR-156628 1 Reactome stable identifier. Use this 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-156628.1 1 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 GENE ONTOLOGY GO:0004776 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 LEFT-TO-RIGHT 6.2.1.5 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> ACTIVATION SUCLA2:SUCLG1 Reactome DB_ID: 10430006 1 sucla2 SUCLA2 Q6P4J7 Reactome DB_ID: 10430004 UniProt:Q6P4J7 sucla2 UniProt Q6P4J7 53 EQUAL 463 EQUAL Reactome Database ID Release 81 10430004 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10430004 Reactome R-XTR-156624 1 Reactome stable identifier. Use this 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-156624.1 1 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 GENE ONTOLOGY GO:0004775 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 LEFT-TO-RIGHT 1.3.5.1 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> FUMA Fumarate fumaric acid Trans-butenedioic acid Reactome DB_ID: 113588 fumaric acid [ChEBI:18012] fumaric acid ChEBI CHEBI:18012 Reactome Database ID Release 81 113588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113588 Reactome R-ALL-113588 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113588.3 COMPOUND C00122 ACTIVATION SDH complex (ox.) Reactome DB_ID: 10429993 sdhd SDHD Q6P355 Reactome DB_ID: 10429991 UniProt:Q6P355 sdhd UniProt Q6P355 57 EQUAL 159 EQUAL Reactome Database ID Release 81 10429991 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429991 Reactome R-XTR-70989 1 Reactome stable identifier. Use this 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-70989.1 1 sdhc SDHC F6U5J7 Reactome DB_ID: 10429987 UniProt:F6U5J7 sdhc UniProt F6U5J7 30 EQUAL 169 EQUAL Reactome Database ID Release 81 10429987 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429987 Reactome R-XTR-70988 1 Reactome stable identifier. Use this 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-70988.1 1 Succinate dehydrogenase Iron Sulphur (subunit B) Reactome DB_ID: 10429983 sdhb SDHB B0BM36 Reactome DB_ID: 10429981 UniProt:B0BM36 sdhb UniProt B0BM36 29 EQUAL 280 EQUAL Reactome Database ID Release 81 10429981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429981 Reactome R-XTR-70985 1 Reactome stable identifier. Use this 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-70985.1 1 Iron Sulfur Cluster Iron Sulphur Cluster Reactome DB_ID: 113591 Reactome Database ID Release 81 113591 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113591 Reactome R-ALL-113591 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113591.2 ChEBI 30408 1 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 1 Succinate dehydrogenase flavoprotein (subunit A), oxidised Reactome DB_ID: 10429977 FAD Flavin adenine dinucleotide FAD(3-) Reactome DB_ID: 113597 Reactome Database ID Release 81 113597 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113597 Reactome R-ALL-113597 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113597.3 COMPOUND C00016 1 sdha SDHA Q28ED0 Reactome DB_ID: 10429975 UniProt:Q28ED0 sdha UniProt Q28ED0 44 EQUAL 664 EQUAL Reactome Database ID Release 81 10429975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429975 Reactome R-XTR-70983 1 Reactome stable identifier. Use this 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-70983.1 1 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 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 GENE ONTOLOGY GO:0008177 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 LEFT-TO-RIGHT 4.2.1.2 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> MAL (S)-Malate (S)-malic acid L-Malate L-Apple acid L-Malic acid L-2-Hydroxybutanedioic acid Reactome DB_ID: 113544 Reactome Database ID Release 81 113544 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113544 Reactome R-ALL-113544 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113544.4 COMPOUND C00149 ACTIVATION FH tetramer Reactome DB_ID: 10429968 FH map1lc3c A0A6I8RSB2 Reactome DB_ID: 10429966 UniProt:A0A6I8RSB2 map1lc3c UniProt A0A6I8RSB2 45 EQUAL 510 EQUAL Reactome Database ID Release 81 10429966 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429966 Reactome R-XTR-70980 1 Reactome stable identifier. Use this 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-70980.1 4 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 GENE ONTOLOGY GO:0004333 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 LEFT-TO-RIGHT 4.2.1.2 (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> ACTIVATION 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). LEFT-TO-RIGHT 1.1.1.37 (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> ACTIVATION MDH2 dimer Reactome DB_ID: 10429959 mdh2 MDH2 F6T7F0 Reactome DB_ID: 10429957 UniProt:F6T7F0 mdh2 UniProt F6T7F0 25 EQUAL 338 EQUAL Reactome Database ID Release 81 10429957 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10429957 Reactome R-XTR-70977 1 Reactome stable identifier. Use this 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-70977.1 2 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 GENE ONTOLOGY GO:0030060 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 LEFT-TO-RIGHT 1.1.1.37 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> ACTIVATION 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 LEFT-TO-RIGHT 1.1.1.40 1.1.1.38 4.1.1.112 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> ACTIVATION FAHD1:Mg2+ dimer Reactome DB_ID: 10517022 FAHD1:Mg2+ Reactome DB_ID: 10517020 fahd1 FAHD1 A0A6I8PLR1 Reactome DB_ID: 10517018 UniProt:A0A6I8PLR1 fahd1 UniProt A0A6I8PLR1 28 EQUAL 224 EQUAL Reactome Database ID Release 81 10517018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517018 Reactome R-XTR-9012048 1 Reactome stable identifier. Use this 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-9012048.1 1 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 2 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 GENE ONTOLOGY GO:0008948 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 LEFT-TO-RIGHT 1.1.1.38 1.1.1.39 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> ACTIVATION ME2:Mg2+ tetramer Reactome DB_ID: 10517048 ME2:Mg2+ dimer Reactome DB_ID: 10517046 ME2:Mg2+ Reactome DB_ID: 10517044 me2 ME2 B7ZUK1 Reactome DB_ID: 10517042 UniProt:B7ZUK1 me2 UniProt B7ZUK1 19 EQUAL 584 EQUAL Reactome Database ID Release 81 10517042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517042 Reactome R-XTR-9012080 1 Reactome stable identifier. Use this 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-9012080.1 1 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 2 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 2 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 GENE ONTOLOGY GO:0004471 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 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 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 LEFT-TO-RIGHT 1.1.1.40 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> ACTIVATION ME3:Mg2+ tetramer Reactome DB_ID: 10517076 ME3:Mg2+ dimer Reactome DB_ID: 10517074 ME3:Mg2+ Reactome DB_ID: 10517072 1 me3 ME3 A0A6I8Q7X5 Reactome DB_ID: 10517070 UniProt:A0A6I8Q7X5 me3 UniProt A0A6I8Q7X5 1 EQUAL 604 EQUAL Reactome Database ID Release 81 10517070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10517070 Reactome R-XTR-9012082 1 Reactome stable identifier. Use this 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-9012082.1 1 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 2 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 2 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 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 GENE ONTOLOGY GO:0006099 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 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> LEFT-TO-RIGHT 1.1.99.2 (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> 2HG (S)-2-hydroxyglutarate (S)-2-hydroxyglutaric acid Reactome DB_ID: 880013 (S)-2-hydroxyglutaric acid [ChEBI:32797] (S)-2-hydroxyglutaric acid ChEBI CHEBI:32797 Reactome Database ID Release 81 880013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880013 Reactome R-ALL-880013 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-880013.3 FADH2 FADH2(2-) Reactome DB_ID: 31649 FADH2(2-) [ChEBI:58307] FADH2(2-) 1,5-dihydro-FAD(2-) 1,5-dihydro-FAD dianion FADH2 dianion (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 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) dihydroflavin adenine dinucleotide dianion dihydroflavin adenine dinucleotide(2-) FADH2 ChEBI CHEBI:58307 Reactome Database ID Release 81 31649 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=31649 Reactome R-ALL-31649 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-31649.3 COMPOUND C01352 ACTIVATION l2hgdh L2HGDH F6QMX5 Reactome DB_ID: 10460183 UniProt:F6QMX5 l2hgdh UniProt F6QMX5 52 EQUAL 463 EQUAL Reactome Database ID Release 81 10460183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460183 Reactome R-XTR-879993 1 Reactome stable identifier. Use this 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-879993.1 GENE ONTOLOGY GO:0047545 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 LEFT-TO-RIGHT 1.1.99.39 (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> 2HG (R)-2-hydroxyglutarate (R)-2-hydroxyglutaric acid Reactome DB_ID: 879997 (R)-2-hydroxyglutaric acid [ChEBI:32796] (R)-2-hydroxyglutaric acid (R)-2-Hydroxyglutarate ChEBI CHEBI:32796 Reactome Database ID Release 81 879997 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879997 Reactome R-ALL-879997 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879997.3 ACTIVATION d2hgdh D2HGDH A0A6I8SE28 Reactome DB_ID: 10460174 UniProt:A0A6I8SE28 d2hgdh UniProt A0A6I8SE28 14 EQUAL 521 EQUAL Reactome Database ID Release 81 10460174 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460174 Reactome R-XTR-880006 1 Reactome stable identifier. Use this 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-880006.1 GENE ONTOLOGY GO:0051990 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 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 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 Zn2+ Zn++ zinc(2+) Zinc ion Zn(II) Reactome DB_ID: 880067 Reactome Database ID Release 81 880067 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880067 Reactome R-ALL-880067 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-880067.3 COMPOUND C00038 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 Co2+ cobalt cobalt atom Reactome DB_ID: 880069 cobalt atom [ChEBI:27638] cobalt atom ChEBI CHEBI:27638 Reactome Database ID Release 81 880069 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880069 Reactome R-ALL-880069 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-880069.3 LEFT-TO-RIGHT 1.1.99.24 (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> SUCCSA succinate semialdehyde succinic semialdehyde 4-oxobutanoate Reactome DB_ID: 880046 4-oxobutanoate [ChEBI:57706] 4-oxobutanoate succinate semialdehyde ChEBI CHEBI:57706 Reactome Database ID Release 81 880046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880046 Reactome R-ALL-880046 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-880046.4 HBUT 4-hydroxybutyrate Reactome DB_ID: 880041 4-hydroxybutyrate [ChEBI:16724] 4-hydroxybutyrate gamma-hydroxybutyrate 4-hydroxybutanoate ChEBI CHEBI:16724 Reactome Database ID Release 81 880041 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=880041 Reactome R-ALL-880041 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-880041.3 ACTIVATION adhfe1 A0A7D9NK53 Reactome DB_ID: 10460167 UniProt:A0A7D9NK53 adhfe1 UniProt A0A7D9NK53 Reactome Database ID Release 81 10460167 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10460167 Reactome R-XTR-880020 1 Reactome stable identifier. Use this 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-880020.1 GENE ONTOLOGY GO:0047988 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 LEFT-TO-RIGHT 1.1.99.24 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> ACTIVATION 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). 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 GENE ONTOLOGY GO:0006103 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 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 GENE ONTOLOGY GO:0044237 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. 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 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 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> LEFT-TO-RIGHT 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> 4Fe-4S 4Iron-4Sulfur Cluster Reactome DB_ID: 169274 Reactome Database ID Release 81 169274 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=169274 Reactome R-ALL-169274 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-169274.2 ChEBI 30408 nubpl NUBPL Q0P4L5 Reactome DB_ID: 10497049 UniProt:Q0P4L5 nubpl UniProt Q0P4L5 39 EQUAL 319 EQUAL Reactome Database ID Release 81 10497049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10497049 Reactome R-XTR-5689133 1 Reactome stable identifier. Use this 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-5689133.1 NUBPL:4Fe-4S Reactome DB_ID: 10497051 1 1 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 LEFT-TO-RIGHT 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> Converted from EntitySet in Reactome NDUF subunits Reactome DB_ID: 10500256 ndufs2 NDUFS2 A0A6I8PZD9 Reactome DB_ID: 10438087 UniProt:A0A6I8PZD9 ndufs2 UniProt A0A6I8PZD9 34 EQUAL 463 EQUAL Reactome Database ID Release 81 10438087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438087 Reactome R-XTR-6788520 1 Reactome stable identifier. Use this 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-6788520.1 ndufs7 NDUFS7 F6ZTQ5 Reactome DB_ID: 10438097 UniProt:F6ZTQ5 ndufs7 UniProt F6ZTQ5 39 EQUAL 213 EQUAL Reactome Database ID Release 81 10438097 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438097 Reactome R-XTR-6788521 1 Reactome stable identifier. Use this 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-6788521.1 ndufs8 NDUFS8 A0A6I8SP86 Reactome DB_ID: 10438103 UniProt:A0A6I8SP86 ndufs8 UniProt A0A6I8SP86 35 EQUAL 210 EQUAL Reactome Database ID Release 81 10438103 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438103 Reactome R-XTR-6788526 1 Reactome stable identifier. Use this 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-6788526.1 Reactome Database ID Release 81 10500256 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10500256 Reactome R-XTR-6788518 1 Reactome stable identifier. Use this 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-6788518.1 Converted from EntitySet in Reactome NDUF:4Fe-4S subunits Reactome DB_ID: 10500258 NDUFS2:4Fe-4S Reactome DB_ID: 10438089 1 1 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 NDUFS7:4Fe-4S Reactome DB_ID: 10438099 1 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 NDUFS8:2x4Fe-4S Reactome DB_ID: 10438105 1 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 Database ID Release 81 10500258 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10500258 Reactome R-XTR-6788527 1 Reactome stable identifier. Use this 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-6788527.1 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 LEFT-TO-RIGHT 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> 2 ndufv2 NDUFV2 Q28HQ2 Reactome DB_ID: 10437945 UniProt:Q28HQ2 ndufv2 UniProt Q28HQ2 33 EQUAL 249 EQUAL Reactome Database ID Release 81 10437945 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437945 Reactome R-XTR-163939 1 Reactome stable identifier. Use this 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-163939.1 me1 NDUFV1 F6WDT0 Reactome DB_ID: 10437939 UniProt:F6WDT0 me1 UniProt F6WDT0 21 EQUAL 464 EQUAL Reactome Database ID Release 81 10437939 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437939 Reactome R-XTR-163926 1 Reactome stable identifier. Use this 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-163926.1 FMN flavin mononucleotide riboflavin-5-phosphate Reactome DB_ID: 76629 FMN(3-) [ChEBI:58210] FMN(3-) riboflavin 5'-phosphate(3-) 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 flavin mononucleotide trianion riboflavin 5'-monophosphate(3-) flavin mononucleotide(3-) riboflavin 5'-phosphate trianion 1-deoxy-1-(7,8-dimethyl-2,4-dioxo-2H-benzo[g]pteridin-3-id-10(4H)-yl)-5-O-phosphonato-D-ribitol FMN FMN trianion riboflavin 5'-monophosphate trianion ChEBI CHEBI:58210 Reactome Database ID Release 81 76629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76629 Reactome R-ALL-76629 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76629.3 COMPOUND C00061 NDUFV1:4Fe-4S:FMN Reactome DB_ID: 10437941 1 1 4Fe-4S 4Iron-4Sulfur Cluster Reactome DB_ID: 164292 Reactome Database ID Release 81 164292 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164292 Reactome R-ALL-164292 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-164292.2 ChEBI 30408 1 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 2 NDUFV2:4Fe-4S Reactome DB_ID: 10437947 1 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 LEFT-TO-RIGHT 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> NDUFAF7:NDUFS2:2x4Fe-4S Reactome DB_ID: 10503508 Q5BKM6 ndufaf7 NDUFAF7 Reactome DB_ID: 10503506 UniProt:Q5BKM6 ndufaf7 UniProt Q5BKM6 47 EQUAL 441 EQUAL Reactome Database ID Release 81 10503506 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503506 Reactome R-XTR-6788525 1 Reactome stable identifier. Use this 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-6788525.1 1 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 NDUFA9:FAD Reactome DB_ID: 10438083 1 ndufa9 NDUFA9 A0A6I8QSQ5 Reactome DB_ID: 10438081 UniProt:A0A6I8QSQ5 ndufa9 UniProt A0A6I8QSQ5 36 EQUAL 377 EQUAL Reactome Database ID Release 81 10438081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438081 Reactome R-XTR-163942 1 Reactome stable identifier. Use this 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-163942.1 1 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 ndufs3 NDUFS3 Q6P613 Reactome DB_ID: 10438093 UniProt:Q6P613 ndufs3 UniProt Q6P613 37 EQUAL 264 EQUAL Reactome Database ID Release 81 10438093 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438093 Reactome R-XTR-163927 1 Reactome stable identifier. Use this 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-163927.1 IP subcomplex Reactome DB_ID: 10503510 1 1 1 1 1 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 LEFT-TO-RIGHT 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> B5DEA5 ndufaf4 NDUFAF4 Reactome DB_ID: 10503518 UniProt:B5DEA5 ndufaf4 UniProt B5DEA5 1 EQUAL 175 EQUAL Reactome Database ID Release 81 10503518 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503518 Reactome R-XTR-5689124 1 Reactome stable identifier. Use this 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-5689124.1 Q6DFN1 ndufaf3 NDUFAF3 Reactome DB_ID: 10503514 UniProt:Q6DFN1 ndufaf3 UniProt Q6DFN1 1 EQUAL 184 EQUAL Reactome Database ID Release 81 10503514 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503514 Reactome R-XTR-5689126 1 Reactome stable identifier. Use this 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-5689126.1 TIMMDC1 A0A803JQK5 Reactome DB_ID: 10503522 UniProt:A0A803JQK5 UniProt A0A803JQK5 1 EQUAL 285 EQUAL Reactome Database ID Release 81 10503522 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503522 Reactome R-XTR-5689720 1 Reactome stable identifier. Use this 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-5689720.1 Intermediate 1 Reactome DB_ID: 10503524 1 1 1 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 LEFT-TO-RIGHT 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> Intermediate 2 Reactome DB_ID: 10503526 1 HP subcomplex Reactome DB_ID: 10438077 ndufb9 NDUFB9 Q0VFA9 Reactome DB_ID: 10438041 UniProt:Q0VFA9 ndufb9 UniProt Q0VFA9 2 EQUAL 179 EQUAL Reactome Database ID Release 81 10438041 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438041 Reactome R-XTR-60176 1 Reactome stable identifier. Use this 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-60176.1 1 ndufa2 NDUFA2 A4IH72 Reactome DB_ID: 10438001 UniProt:A4IH72 ndufa2 UniProt A4IH72 2 EQUAL 99 EQUAL Reactome Database ID Release 81 10438001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438001 Reactome R-XTR-60178 1 Reactome stable identifier. Use this 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-60178.1 1 ndufb4 NDUFB4 A4QNM1 Reactome DB_ID: 10438027 UniProt:A4QNM1 ndufb4 UniProt A4QNM1 2 EQUAL 129 EQUAL Reactome Database ID Release 81 10438027 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438027 Reactome R-XTR-59934 1 Reactome stable identifier. Use this 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-59934.1 1 ndufc2 NDUFC2 A0A1B8Y3G3 Reactome DB_ID: 10438053 UniProt:A0A1B8Y3G3 ndufc2 UniProt A0A1B8Y3G3 1 EQUAL 119 EQUAL Reactome Database ID Release 81 10438053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438053 Reactome R-XTR-59860 1 Reactome stable identifier. Use this 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-59860.1 1 ndufa3 NDUFA3 A0A6I8SQC4 Reactome DB_ID: 10438005 UniProt:A0A6I8SQC4 ndufa3 UniProt A0A6I8SQC4 2 EQUAL 84 EQUAL Reactome Database ID Release 81 10438005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438005 Reactome R-XTR-60180 1 Reactome stable identifier. Use this 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-60180.1 1 Ghost homologue of NDUFA8 Reactome DB_ID: 10438013 Reactome Database ID Release 81 10438013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438013 Reactome R-XTR-60627 1 Reactome stable identifier. Use this 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-60627.1 1 NDUFA10:FAD Reactome DB_ID: 10438067 1 Ghost homologue of NDUFA10 Reactome DB_ID: 10438065 Reactome Database ID Release 81 10438065 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438065 Reactome R-XTR-163937 1 Reactome stable identifier. Use this 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-163937.1 1 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 1 ndufb7 NDUFB7 A4II52 Reactome DB_ID: 10438035 UniProt:A4II52 ndufb7 UniProt A4II52 2 EQUAL 137 EQUAL Reactome Database ID Release 81 10438035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438035 Reactome R-XTR-59940 1 Reactome stable identifier. Use this 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-59940.1 1 ndufa13 NDUFA13 A0A803JG20 Reactome DB_ID: 10438057 UniProt:A0A803JG20 ndufa13 UniProt A0A803JG20 2 EQUAL 144 EQUAL Reactome Database ID Release 81 10438057 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438057 Reactome R-XTR-59936 1 Reactome stable identifier. Use this 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-59936.1 1 ndufa1 NDUFA1 A0A803JX78 Reactome DB_ID: 10437997 UniProt:A0A803JX78 ndufa1 UniProt A0A803JX78 1 EQUAL 70 EQUAL Reactome Database ID Release 81 10437997 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437997 Reactome R-XTR-60212 1 Reactome stable identifier. Use this 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-60212.1 1 NDUFA7 A0A803JVE2 Reactome DB_ID: 10438011 UniProt:A0A803JVE2 UniProt A0A803JVE2 2 EQUAL 113 EQUAL Reactome Database ID Release 81 10438011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438011 Reactome R-XTR-59858 1 Reactome stable identifier. Use this 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-59858.1 1 elp6 NDUFB10 A4QNF0 Reactome DB_ID: 10438045 UniProt:A4QNF0 elp6 UniProt A4QNF0 1 EQUAL 172 EQUAL Reactome Database ID Release 81 10438045 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438045 Reactome R-XTR-60194 1 Reactome stable identifier. Use this 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-60194.1 1 B3DM83 ndufa11 NDUFA11 Reactome DB_ID: 10438061 UniProt:B3DM83 ndufa11 UniProt B3DM83 2 EQUAL 141 EQUAL Reactome Database ID Release 81 10438061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438061 Reactome R-XTR-163923 1 Reactome stable identifier. Use this 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-163923.1 1 Q6AZL3 ndufab1 NDUFAB1 Reactome DB_ID: 10438017 UniProt:Q6AZL3 ndufab1 UniProt Q6AZL3 69 EQUAL 156 EQUAL Reactome Database ID Release 81 10438017 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438017 Reactome R-XTR-163925 1 Reactome stable identifier. Use this 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-163925.1 1 ndufb5 NDUFB5 F6V6L5 Reactome DB_ID: 10438031 UniProt:F6V6L5 ndufb5 UniProt F6V6L5 47 EQUAL 189 EQUAL Reactome Database ID Release 81 10438031 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438031 Reactome R-XTR-163944 1 Reactome stable identifier. Use this 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-163944.1 1 ndufb1 NDUFB1 A0A803J5X2 Reactome DB_ID: 10438071 UniProt:A0A803J5X2 ndufb1 UniProt A0A803J5X2 1 EQUAL 58 EQUAL Reactome Database ID Release 81 10438071 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438071 Reactome R-XTR-60214 1 Reactome stable identifier. Use this 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-60214.1 1 ndufb2 NDUFB2 F7A0M7 Reactome DB_ID: 10438021 UniProt:F7A0M7 ndufb2 UniProt F7A0M7 34 EQUAL 105 EQUAL Reactome Database ID Release 81 10438021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438021 Reactome R-XTR-163941 1 Reactome stable identifier. Use this 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-163941.1 1 NDUFC1 A0A6I8PY53 Reactome DB_ID: 10438049 UniProt:A0A6I8PY53 UniProt A0A6I8PY53 28 EQUAL 76 EQUAL Reactome Database ID Release 81 10438049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438049 Reactome R-XTR-163940 1 Reactome stable identifier. Use this 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-163940.1 1 Ghost homologue of NDUFB11 Reactome DB_ID: 10438063 Reactome Database ID Release 81 10438063 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438063 Reactome R-XTR-163933 1 Reactome stable identifier. Use this 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-163933.1 1 Ghost homologue of NDUFB8 Reactome DB_ID: 10438037 Reactome Database ID Release 81 10438037 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438037 Reactome R-XTR-163938 1 Reactome stable identifier. Use this 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-163938.1 1 ndufa5 NDUFA5 Q28BN5 Reactome DB_ID: 10438075 UniProt:Q28BN5 ndufa5 UniProt Q28BN5 2 EQUAL 116 EQUAL Reactome Database ID Release 81 10438075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438075 Reactome R-XTR-60599 1 Reactome stable identifier. Use this 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-60599.1 1 Ghost homologue of NDUFB3 Reactome DB_ID: 10438023 Reactome Database ID Release 81 10438023 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438023 Reactome R-XTR-59930 1 Reactome stable identifier. Use this 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-59930.1 1 Ghost homologue of NDUFA6 Reactome DB_ID: 10438007 Reactome Database ID Release 81 10438007 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10438007 Reactome R-XTR-59932 1 Reactome stable identifier. Use this 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-59932.1 1 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 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 ndufaf5 NDUFAF5 A0A6I8SMN0 Reactome DB_ID: 10503530 UniProt:A0A6I8SMN0 ndufaf5 UniProt A0A6I8SMN0 37 EQUAL 345 EQUAL Reactome Database ID Release 81 10503530 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503530 Reactome R-XTR-5689127 1 Reactome stable identifier. Use this 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-5689127.1 NDUFAF6 A0A6I8SRG6 Reactome DB_ID: 10503534 UniProt:A0A6I8SRG6 UniProt A0A6I8SRG6 45 EQUAL 333 EQUAL Reactome Database ID Release 81 10503534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503534 Reactome R-XTR-5689130 1 Reactome stable identifier. Use this 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-5689130.1 nd1 MT-ND1 Q5G7J0 Reactome DB_ID: 10437993 UniProt:Q5G7J0 nd1 UniProt Q5G7J0 1 EQUAL 318 EQUAL Reactome Database ID Release 81 10437993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437993 Reactome R-XTR-60551 1 Reactome stable identifier. Use this 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-60551.1 315kDa subcomplex Reactome DB_ID: 10503536 1 1 1 1 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). LEFT-TO-RIGHT 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> ndufb6 NDUFB6 Q28HL5 Reactome DB_ID: 10437967 UniProt:Q28HL5 ndufb6 UniProt Q28HL5 2 EQUAL 128 EQUAL Reactome Database ID Release 81 10437967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437967 Reactome R-XTR-59938 1 Reactome stable identifier. Use this 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-59938.1 nd6 MT-ND6 Q5G7H9 Reactome DB_ID: 10437963 UniProt:Q5G7H9 nd6 UniProt Q5G7H9 1 EQUAL 174 EQUAL Reactome Database ID Release 81 10437963 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437963 Reactome R-XTR-60569 1 Reactome stable identifier. Use this 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-60569.1 MCIA complex Reactome DB_ID: 10503562 ecsit ECSIT Q0V9C9 Reactome DB_ID: 10503544 UniProt:Q0V9C9 ecsit UniProt Q0V9C9 49 EQUAL 431 EQUAL Reactome Database ID Release 81 10503544 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503544 Reactome R-XTR-5689047 1 Reactome stable identifier. Use this 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-5689047.1 1 acad9 ACAD9 A0A803JIV0 Reactome DB_ID: 10503540 UniProt:A0A803JIV0 acad9 UniProt A0A803JIV0 1 EQUAL 621 EQUAL Reactome Database ID Release 81 10503540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503540 Reactome R-XTR-5689049 1 Reactome stable identifier. Use this 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-5689049.1 1 Converted from EntitySet in Reactome Homologues of TMEM126B Reactome DB_ID: 10503560 TMEM126B A0A7D9NMF8 Reactome DB_ID: 10503550 UniProt:A0A7D9NMF8 UniProt A0A7D9NMF8 1 EQUAL 230 EQUAL Reactome Database ID Release 81 10503550 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503550 Reactome R-XTR-5689046 1 Reactome stable identifier. Use this 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-5689046.1 TMEM126B A0A803K978 Reactome DB_ID: 10503554 UniProt:A0A803K978 UniProt A0A803K978 1 EQUAL 230 EQUAL Reactome Database ID Release 81 10503554 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503554 Reactome R-XTR-5689046-2 1 Reactome stable identifier. Use this 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-5689046-2.1 tmem126a TMEM126B A0A803KIF1 Reactome DB_ID: 10503558 UniProt:A0A803KIF1 tmem126a UniProt A0A803KIF1 1 EQUAL 230 EQUAL Reactome Database ID Release 81 10503558 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503558 Reactome R-XTR-5689046-3 1 Reactome stable identifier. Use this 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-5689046-3.1 Reactome Database ID Release 81 10503560 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503560 Reactome R-XTR-5689046-4 1 Reactome stable identifier. Use this 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-5689046-4.1 1 Ghost homologue of NDUFAF1 Reactome DB_ID: 10503546 Reactome Database ID Release 81 10503546 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10503546 Reactome R-XTR-5689050 1 Reactome stable identifier. Use this 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-5689050.1 1 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 COA1:MT-ND2 Reactome DB_ID: 10437977 coa1 COA1 F6YDW6 Reactome DB_ID: 10437975 UniProt:F6YDW6 coa1 UniProt F6YDW6 1 EQUAL 146 EQUAL Reactome Database ID Release 81 10437975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437975 Reactome R-XTR-9708001 1 Reactome stable identifier. Use this 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-9708001.1 1 nd2 MT-ND2 Q5G7I9 Reactome DB_ID: 10437971 UniProt:Q5G7I9 nd2 UniProt Q5G7I9 1 EQUAL 347 EQUAL Reactome Database ID Release 81 10437971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437971 Reactome R-XTR-60553 1 Reactome stable identifier. Use this 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-60553.1 1 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 TMEM186:MT-ND3 Reactome DB_ID: 10437987 nd3 MT-ND3 Q5G7I3 Reactome DB_ID: 10437981 UniProt:Q5G7I3 nd3 UniProt Q5G7I3 1 EQUAL 115 EQUAL Reactome Database ID Release 81 10437981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437981 Reactome R-XTR-60557 1 Reactome stable identifier. Use this 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-60557.1 1 tmem186 TMEM186 A0A6I8QWJ0 Reactome DB_ID: 10437985 UniProt:A0A6I8QWJ0 tmem186 UniProt A0A6I8QWJ0 1 EQUAL 213 EQUAL Reactome Database ID Release 81 10437985 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10437985 Reactome R-XTR-9708009 1 Reactome stable identifier. Use this 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-9708009.1 1 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-9708002.1 370 kDa subcomplex Reactome DB_ID: 10503564 1 1 1 1 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 LEFT-TO-RIGHT 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> 550kDa complex Reactome DB_ID: 10503566 1 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). LEFT-TO-RIGHT 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/paral