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 pyruvatedeh-cplx 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 thiamin 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 [Zhou01] 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 pyruvatedeh-cplx, 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
Fries03: Fries M, Jung HI, Perham RN (2003). "Reaction mechanism of the heterotetrameric (alpha2beta2) E1 component of 2-oxo acid dehydrogenase multienzyme complexes." Biochemistry 42(23);6996-7002. PMID: 12795594
Himmelreich96: Himmelreich R, Hilbert H, Plagens H, Pirkl E, Li BC, Herrmann R (1996). "Complete sequence analysis of the genome of the bacterium Mycoplasma pneumoniae." Nucleic Acids Res 1996;24(22);4420-49. PMID: 8948633
Manolukas88: Manolukas JT, Barile MF, Chandler DK, Pollack JD (1988). "Presence of anaplerotic reactions and transamination, and the absence of the tricarboxylic acid cycle in mollicutes." J Gen Microbiol 1988;134 ( Pt 3);791-800. PMID: 3141576
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
Pollack97: Pollack JD, Williams MV, McElhaney RN (1997). "The comparative metabolism of the mollicutes (Mycoplasmas): the utility for taxonomic classification and the relationship of putative gene annotation and phylogeny to enzymatic function in the smallest free-living cells." Crit Rev Microbiol 1997;23(4);269-354. PMID: 9439886
Zhou01: 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
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
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.
Chun90: Chun K, Mackay N, Willard HF, Robinson BH (1990). "Isolation, characterization and chromosomal localization of cDNA clones for the E1 beta subunit of the pyruvate dehydrogenase complex." Eur J Biochem 194(2);587-92. PMID: 1702713
Ciszak03: Ciszak EM, Korotchkina LG, Dominiak PM, Sidhu S, Patel MS (2003). "Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase." J Biol Chem 278(23);21240-6. PMID: 12651851
Coppel88: Coppel RL, McNeilage LJ, Surh CD, Van de Water J, Spithill TW, Whittingham S, Gershwin ME (1988). "Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase." Proc Natl Acad Sci U S A 85(19);7317-21. PMID: 3174635
Dahl87: Dahl HH, Hunt SM, Hutchison WM, Brown GK (1987). "The human pyruvate dehydrogenase complex. Isolation of cDNA clones for the E1 alpha subunit, sequence analysis, and characterization of the mRNA." J Biol Chem 262(15);7398-403. PMID: 3034892
De88b: De Meirleir L, MacKay N, Lam Hon Wah AM, Robinson BH (1988). "Isolation of a full-length complementary DNA coding for human E1 alpha subunit of the pyruvate dehydrogenase complex." J Biol Chem 263(4);1991-5. PMID: 2828359
Harmych02: Harmych S, Arnette R, Komuniecki R (2002). "Role of dihydrolipoyl dehydrogenase (E3) and a novel E3-binding protein in the NADH sensitivity of the pyruvate dehydrogenase complex from anaerobic mitochondria of the parasitic nematode, Ascaris suum." Mol Biochem Parasitol 125(1-2);135-46. PMID: 12467981
Harris97: Harris RA, Bowker-Kinley MM, Wu P, Jeng J, Popov KM (1997). "Dihydrolipoamide dehydrogenase-binding protein of the human pyruvate dehydrogenase complex. DNA-derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex." J Biol Chem 272(32);19746-51. PMID: 9242632
Head05: Head RA, Brown RM, Zolkipli Z, Shahdadpuri R, King MD, Clayton PT, Brown GK (2005). "Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency." Ann Neurol 58(2);234-41. PMID: 16049940
Ho88: Ho L, Javed AA, Pepin RA, Thekkumkara TJ, Raefsky C, Mole JE, Caliendo AM, Kwon MS, Kerr DS, Patel MS (1988). "Identification of a cDNA clone for the beta-subunit of the pyruvate dehydrogenase component of human pyruvate dehydrogenase complex." Biochem Biophys Res Commun 150(3);904-8. PMID: 2829898
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