This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: pyruvate dehydrogenase complex, acetyl-CoA biosynthesis I (pyruvate dehydrogenase complex)
|Superclasses:||Degradation/Utilization/Assimilation → Carboxylates Degradation|
|Generation of Precursor Metabolites and Energy → Acetyl-CoA Biosynthesis|
2-oxo acid dehydrogenase complexes convert 2-oxo acids to the corresponding acyl-CoA derivatives and produce NADH and CO2 in an irreversible reaction. Five members of this family are known at present, including the pyruvate dehydrogenase complex (PDHC - this pathway), the 2-oxoglutarate dehydrogenase complex (OGDHC), the branched-chain α-keto acid dehydrogenase complex (BCDHC), the glycine cleavage complex (GDHC), and the acetoin dehydrogenase complex (ADHC). They all function at strategic points in (usually aerobic) catabolic pathways and are subject to stringent control [deKok98].
With the exception of GDHC, the 2-oxo acid dehydrogenase complexes share a common structure. They consist of three main components, namely a 2-oxo acid dehydrogenase (E1), a dihydrolipoamide acyltransferase (E2), and dihydrolipoamide dehydrogenase (E3). In Gram-positive bacteria and mitochondria, the E1 component is a heterodimer composed of two subunits, while in Gram-negative bacteria it is made of a single type of subunit.
In all cases described so far, many copies of each subunit assemble to form the full complex. For example, the Escherichia coli K-12 pyruvate dehydrogenase comprises 24, 24, and 12 units of the E1, E2, and E3 components, respectively. The core of the complex is made of either 24 (Gram-negative bacteria) or 60 (mitochondria) E2 units, which contain the lipoyl active site in the form of lipoyllysine, as well as binding sites for the other two subunits. E1, which contains a thiamine diphosphate cofactor, catalyzes the binding of the 2-oxo acid to the lipoyl group of E2, which then transfers an acyl group (the nature of the acyl group depends on the particular enzyme) to coenzyme A, forming an acyl-CoA. During this transfer, the lipoyl group is reduced to dihydrolipoyl. E3 then transfers the protons to NAD, forming NADH and restoring the dihydrolipoyllysine group back to lipoyllysine.
Cryoelectron microscopy of PDHC from Geobacillus stearothermophilus [Milne02] and ox kidney [Zhou01a] has revealed that the E2 inner core is surrounded by an outer shell of E1 and E3 components, with the lipoyl domains confined to the annular space between them where they must make successive journeys between the three types of active sites (E1-E3), which are physically far apart [Fries03].
About This Pathway
In the pathway illustrated here, pyruvate is converted to acetyl-CoA and CO2, a key reaction of central metabolism, which links the substrate-level phosphorylation pathway glycolysis (which ends with the generation of pyruvate) to the TCA cycle I (prokaryotic), which accepts the input of acetyl-CoA.
The pyruvate dehydrogenase, which in Escherichia coli consists of 24 E1 subunits, 24 E2 subunits, and 12 E3 subunits, catalyzes three reactions that constitute a cycle. The three reactions can be summarized by the reaction
During aerobic growth of Escherichia coli the cycle is an essential source of acetyl-CoA to feed the TCA cycle I (prokaryotic) and thereby to satisfy the cellular requirements for the precursor metabolites it forms. Mutant strains defective in the complex require an exogenous source of acetate during aerobic growth, but not under anaerobic conditions,since during anaerobic growth pyruvate formate lyase generates acetyl-CoA from pyruvate. Mutant strains lacking pyruvate formate lyase have the reverse phenotype [ECOSAL].
Plants have two forms of pyruvate dehydrogenase complex, one in the plastid and the other in the mitochondrion. The two complexes have distinct physiological roles. The plastid pyruvate dehydrogenase complex provides the main acetyl-CoA source for de novo fatty acid biosynthesis ( fatty acid biosynthesis initiation I). The mitochondrial complex provides acetyl-CoA for the TCA cycle I (prokaryotic) cycle and NADH for oxidative phosphorylation. Both complexes are feedback inhibited by acetyl-CoA and NADH. However the two complexes differ in other aspects of enzyme characteristics. The mitochondrial complex but not the plastid one is regulated by phosphorylation. The plastid complex requires higher Mg2+ concentration and more alkaline pH for maximal enzyme activity [TovarMendez03].
Unification Links: EcoCyc:PYRUVDEHYD-PWY
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Milne02: Milne JL, Shi D, Rosenthal PB, Sunshine JS, Domingo GJ, Wu X, Brooks BR, Perham RN, Henderson R, Subramaniam S (2002). "Molecular architecture and mechanism of an icosahedral pyruvate dehydrogenase complex: a multifunctional catalytic machine." EMBO J 21(21);5587-98. PMID: 12411477
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Zhou01a: Zhou ZH, McCarthy DB, O'Connor CM, Reed LJ, Stoops JK (2001). "The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes." Proc Natl Acad Sci U S A 98(26);14802-7. PMID: 11752427
Adamson86: Adamson SR, Holmes CF, Stevenson KJ (1986). "Acetylatable lipoic acid residues interact directly with lipoamide dehydrogenase in the pyruvate dehydrogenase multienzyme complex of Escherichia coli." Biochem Cell Biol 64(3);250-5. PMID: 3087386
Akiyama80: Akiyama SK, Hammes GG (1980). "Elementary steps in the reaction mechanism of the pyruvate dehydrogenase multienzyme complex from Escherichia coli: kinetics of acetylation and deacetylation." Biochemistry 1980;19(18);4208-13. PMID: 6998493
Allen89: Allen AG, Perham RN, Allison N, Miles JS, Guest JR (1989). "Reductive acetylation of tandemly repeated lipoyl domains in the pyruvate dehydrogenase multienzyme complex of Escherichia coli is random order." J Mol Biol 208(4);623-33. PMID: 2509711
Angelides79: Angelides KJ, Akiyama SK, Hammes GG (1979). "Subunit stoichiometry and molecular weight of the pyruvate dehydrogenase multienzyme complex from Escherichia coli." Proc Natl Acad Sci U S A 1979;76(7);3279-83. PMID: 386335
Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699
Bates77: Bates DL, Danson MJ, Hale G, Hooper EA, Perham RN (1977). "Self-assembly and catalytic activity of the pyruvate dehydrogenase multienzyme complex of Escherichia coli." Nature 268(5618);313-6. PMID: 329143
Brown04: Brown RM, Head RA, Boubriak II, Leonard JV, Thomas NH, Brown GK (2004). "Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency." Hum Genet 115(2);123-7. PMID: 15138885
Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043
CaJacob85: CaJacob CA, Frey PA, Hainfeld JF, Wall JS, Yang H (1985). "Escherichia coli pyruvate dehydrogenase complex: particle masses of the complex and component enzymes measured by scanning transmission electron microscopy." Biochemistry 1985;24(10);2425-31. PMID: 3925985
CaJacob85a: CaJacob CA, Gavino GR, Frey PA (1985). "Pyruvate dehydrogenase complex of Escherichia coli. Thiamin pyrophosphate and NADH-dependent hydrolysis of acetyl-CoA." J Biol Chem 260(27);14610-15. PMID: 3902834
Camp88: Camp, Pamela J, Miernyk, Jan A, Randall, Douglas D (1988). "Some kinetic and regulatory properties of the pea chloroplast pyruvate dehydrogenase complex." Biochimica et Biophysica Acta, 933:269-275.
Carothers89: Carothers DJ, Pons G, Patel MS (1989). "Dihydrolipoamide dehydrogenase: functional similarities and divergent evolution of the pyridine nucleotide-disulfide oxidoreductases." Arch Biochem Biophys 1989;268(2);409-25. PMID: 2643922
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