BioPAX pathway converted from "lipo-PDH decarboxylates PYR to Ac-CoA" in the Reactome database. lipo-PDH decarboxylates PYR to Ac-CoA lipo-PDH decarboxylates PYR to Ac-CoA pyruvate + CoASH + NAD+ => acetylCoA + CO2 + NADH + H+ Oxidative decarboxylation of pyruvate to acetyl CoA by pyruvate dehydrogenase 线粒体丙酮酸德hydrogenase 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). Authored: Birney, E, Schmidt, EE, 2003-01-28 00:00:00 Edited: D'Eustachio, P, 0000-00-00 00:00:00 Reactome DB_ID: 113557 1 mitochondrial matrix GO 0005759 pyruvate [ChEBI:15361] pyruvate 2-oxopropanoate 2-oxopropanoic acid, ion(1-) Reactome //www.joaskin.com ChEBI 15361 Reactome DB_ID: 113526 1 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Reactome DB_ID: 29374 1 coenzyme A [ChEBI:15346] coenzyme A ChEBI 15346 Reactome DB_ID: 113559 1 acetyl-CoA [ChEBI:15351] acetyl-CoA ChEBI 15351 Reactome DB_ID: 29362 1 NADH(2-) [ChEBI:57945] NADH(2-) NADH dianion adenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADH ChEBI 57945 Reactome DB_ID: 29376 1 carbon dioxide [ChEBI:16526] carbon dioxide ChEBI 16526 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 70070 lipo-PDH [mitochondrial matrix] lipo-PDH pyruvate dehydrogenase complex Reactome DB_ID: 70059 12 UniProt:O00330 PDHX PDHX PDHX PDX1 FUNCTION Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. This specific binding is essential for a functional PDH complex.SUBUNIT Part of the inner core of the multimeric pyruvate dehydrogenase complex that is composed of about 48 DLAT and 12 PDHX molecules (PubMed:14638692, PubMed:20361979). This core binds multiple copies of pyruvate dehydrogenase (subunits PDH1A and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). Interacts with SIRT4 (PubMed:25525879). Interacts with DLD (PubMed:20385101, PubMed:16263718, PubMed:16442803, PubMed:20160912, PubMed:20361979).PTM Delipoylated at Lys-97 by SIRT4, delipoylation decreases the PHD complex activity.SIMILARITY Belongs to the 2-oxoacid dehydrogenase family. Homo sapiens NCBI Taxonomy 9606 UniProt O00330 Chain Coordinates 54 EQUAL 501 EQUAL Reactome DB_ID: 69971 20 lipo-K-132,K259-DLAT trimer [mitochondrial matrix] lipo-K-132,K259-DLAT trimer pyruvate dehydrogenase E2 trimer Reactome DB_ID: 69969 3 UniProt:P10515 DLAT DLAT DLTA DLAT FUNCTION The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.SUBUNIT Part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (subunits PDH1A and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (PubMed:14638692, PubMed:20361979). Interacts with PDK2 and PDK3 (PubMed:15861126, PubMed:17532006, PubMed:17683942, PubMed:18387944). Interacts with SIRT4 (PubMed:25525879). Interacts with PDHB (PubMed:20160912).PTM Delipoylated at Lys-132 and Lys-259 by SIRT4, delipoylation decreases the PHD complex activity.DISEASE Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex.SIMILARITY Belongs to the 2-oxoacid dehydrogenase family. UniProt P10515 N6-lipoyl-L-lysine at 132 132 EQUAL N6-lipoyl-L-lysine [MOD:00127] N6-lipoyl-L-lysine at 259 259 EQUAL 87 EQUAL 647 EQUAL Reactome Database ID Release 77 69971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=69971 Reactome R-HSA-69971 2 Reactome稳定的标识符。Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69971.2 Reactome DB_ID: 69980 6 aKADH E3 dimer [mitochondrial matrix] aKADH E3 dimer alpha-keto acid dehydrogenase E3 homodimer Reactome DB_ID: 69979 2 aKADH E3 [mitochondrial matrix] aKADH E3 alpha-keto acid dehydrogenase E3 holoenzyme DLD:FAD Reactome DB_ID: 113596 1 FAD [ChEBI:16238] FAD Flavin adenine dinucleotide ChEBI 16238 Reactome DB_ID: 69978 1 UniProt:P09622 DLD DLD PHE3 GCSL DLD LAD FUNCTION Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched-chain amino acid-dehydrogenase complex) (PubMed:15712224, PubMed:16442803, PubMed:16770810, PubMed:17404228, PubMed:20160912, PubMed:20385101). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711). In monomeric form may have additional moonlighting function as serine protease (PubMed:17404228). Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction (By similarity).ACTIVITY REGULATION Disruption of native heterodimer state inhibits primary dihydrolipoamide dehydrogenase activity and induces serine protease activity.SUBUNIT Homodimer (PubMed:15946682). Part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (subunits PDHA (PDHA1 or PDHA2) and PDHB, E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (by non covalent bonds) (PubMed:14638692, PubMed:20361979). The 2-oxoglutarate dehydrogenase complex is composed of OGDH (2-oxoglutarate dehydrogenase; E1), DLST (dihydrolipoamide succinyltransferase; E2) and DLD (dihydrolipoamide dehydrogenase; E3). It contains multiple copies of the three enzymatic components (E1, E2 and E3). In the nucleus, the 2-oxoglutarate dehydrogenase complex associates with KAT2A (PubMed:29211711). Interacts with PDHX (PubMed:20385101, PubMed:16442803, PubMed:20160912, PubMed:20361979).PTM Tyrosine phosphorylated.MISCELLANEOUS The active site is a redox-active disulfide bond.SIMILARITY Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family. UniProt P09622 36 EQUAL 509 EQUAL Reactome Database ID Release 77 69979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=69979 Reactome R-HSA-69979 2 Reactome稳定的标识符。Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69979.2 Reactome Database ID Release 77 69980 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=69980 Reactome R-HSA-69980 2 Reactome稳定的标识符。Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69980.2 Reactome DB_ID: 69968 22 PDH E1 [mitochondrial matrix] PDH E1 pyruvate dehydrogenase E1 complex Reactome DB_ID: 113547 2 thiamine(1+) diphosphate(3-) [ChEBI:58937] thiamine(1+) diphosphate(3-) thiamine diphosphate thiamine diphosphate dianion thiamine diphosphate(2-) ChEBI 58937 Reactome DB_ID: 69967 2 UniProt:P11177 PDHB PDHB PHE1B PDHB FUNCTION The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.SUBUNIT Heterotetramer of two PDHA1 and two PDHB subunits (PubMed:12651851, PubMed:17474719, PubMed:19081061). The heterotetramer interacts with DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (PubMed:14638692). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (PubMed:14638692). Interacts with DLAT (PubMed:20160912). UniProt P11177 31 EQUAL 359 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 8953511 2 PDHA1,2 [mitochondrial matrix] 从Reactome EntitySet转换。每个同义词is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PDHA2 [mitochondrial matrix] PDHA1 [mitochondrial matrix] UniProt P29803 UniProt P08559 Reactome Database ID Release 77 69968 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=69968 Reactome R-HSA-69968 3 Reactome稳定的标识符。Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69968.3 Reactome Database ID Release 77 70070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=70070 Reactome R-HSA-70070 8 Reactome稳定的标识符。Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70070.8 GO 0004738 GO molecular function Reactome Database ID Release 77 450854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=450854 Reactome Database ID Release 77 71397 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=71397 Reactome R-HSA-71397 2 Reactome稳定的标识符。Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-71397.2 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 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 2188967 Pubmed 1990 Structure-function relationships in dihydrolipoamide acyltransferases. Reed, LJ Hackert, ML J Biol Chem 265:8971-4 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 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 15946682 Pubmed 2005 Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations 布劳提根, Chuang, JL Tomchick, DR Machius, M Chuang, DT J Mol Biol 350:543-52