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MetaCyc Pathway: 2-oxoglutarate decarboxylation to succinyl-CoA

Enzyme View:

Pathway diagram: 2-oxoglutarate decarboxylation to succinyl-CoA

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: 2-oxoglutarate dehydrogenase complex, 2-ketoglutarate dehydrogenase complex

Superclasses: Generation of Precursor Metabolites and Energy Respiration

Some taxa known to possess this pathway include ? : Bacillus subtilis , Deinococcus radiodurans , Escherichia coli K-12 substr. MG1655 , Geobacillus stearothermophilus , Homo sapiens , Mus musculus , Pseudomonas aeruginosa , Pseudomonas putida , Rattus norvegicus , Sulfolobus solfataricus , Synechocystis

Expected Taxonomic Range: Archaea , Bacteria , Eukaryota

Summary:
General Background

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), the 2-oxoglutarate dehydrogenase complex (OGDHC - this pathway), 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

The pathway illustrated here presents the reactions catalyzed by the 2-oxoglutarate dehydrogenase complex, a key enzyme of the TCA cycle I (prokaryotic). These reactions can be summarized by the general reaction

2-oxoglutarate + coenzyme A + NAD+ → succinyl-CoA + CO2 + NADH

which is the form commonly found in the TCA cycle.

Unification Links: EcoCyc:PWY-5084

Credits:
Created 16-Jan-2006 by Caspi R , SRI International


References

deKok98: de Kok A, Hengeveld AF, Martin A, Westphal AH (1998). "The pyruvate dehydrogenase multi-enzyme complex from Gram-negative bacteria." Biochim Biophys Acta 1385(2);353-66. PMID: 9655933

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

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

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Ali94: Ali G, Wasco W, Cai X, Szabo P, Sheu KF, Cooper AJ, Gaston SM, Gusella JF, Tanzi RE, Blass JP (1994). "Isolation, characterization, and mapping of gene encoding dihydrolipoyl succinyltransferase (E2k) of human alpha-ketoglutarate dehydrogenase complex." Somat Cell Mol Genet 20(2);99-105. PMID: 8009371

Ambrus09: Ambrus A, Torocsik B, Adam-Vizi V (2009). "Periplasmic cold expression and one-step purification of human dihydrolipoamide dehydrogenase." Protein Expr Purif 63(1);50-7. PMID: 18845259

Brown02a: Brown RM, Head RA, Brown GK (2002). "Pyruvate dehydrogenase E3 binding protein deficiency." Hum Genet 110(2);187-91. PMID: 11935326

Feigenbaum93: Feigenbaum AS, Robinson BH (1993). "The structure of the human dihydrolipoamide dehydrogenase gene (DLD) and its upstream elements." Genomics 17(2);376-81. PMID: 8406489

Hemila90: Hemila H, Palva A, Paulin L, Arvidson S, Palva I (1990). "Secretory S complex of Bacillus subtilis: sequence analysis and identity to pyruvate dehydrogenase." J Bacteriol 172(9);5052-63. PMID: 1697575

Hodgson83: Hodgson JA, Lowe PN, Perham RN (1983). "Wild-type and mutant forms of the pyruvate dehydrogenase multienzyme complex from Bacillus subtilis." Biochem J 211(2);463-72. PMID: 6409095

Koike92: Koike K, Urata Y, Goto S (1992). "Cloning and nucleotide sequence of the cDNA encoding human 2-oxoglutarate dehydrogenase (lipoamide)." Proc Natl Acad Sci U S A 89(5);1963-7. PMID: 1542694

Koike95: Koike K (1995). "The gene encoding human 2-oxoglutarate dehydrogenase: structural organization and mapping to chromosome 7p13-p14." Gene 159(2);261-6. PMID: 7622061

Koike98: Koike K (1998). "Cloning, structure, chromosomal localization and promoter analysis of human 2-oxoglutarate dehydrogenase gene." Biochim Biophys Acta 1385(2);373-84. PMID: 9655939

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Liu93: Liu TC, Kim H, Arizmendi C, Kitano A, Patel MS (1993). "Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient." Proc Natl Acad Sci U S A 90(11);5186-90. PMID: 8506365

Massey60: Massey V, Gibson QH, Veeger C (1960). "Intermediates in the catalytic action of lipoyl dehydrogenase (diaphorase)." Biochem J 77;341-51. PMID: 13767908

Munnich82: Munnich A, Saudubray JM, Taylor J, Charpentier C, Marsac C, Rocchiccioli F, Amedee-Manesme O, Coude FX, Frezal J, Robinson BH (1982). "Congenital lactic acidosis, alpha-ketoglutaric aciduria and variant form of maple syrup urine disease due to a single enzyme defect: dihydrolipoyl dehydrogenase deficiency." Acta Paediatr Scand 71(1);167-71. PMID: 6897145

Nakano93: Nakano K, Takase C, Sakamoto T, Ohta S, Nakagawa S, Ariyama T, Inazawa J, Abe T, Matuda S (1993). "An unspliced cDNA for human dihydrolipoamide succinyltransferase: characterization and mapping of the gene to chromosome 14q24.2-q24.3." Biochem Biophys Res Commun 196(2);527-33. PMID: 8240324

Nakano93a: Nakano K, Matuda S, Sakamoto T, Takase C, Nakagawa S, Ohta S, Ariyama T, Inazawa J, Abe T, Miyata T (1993). "Human dihydrolipoamide succinyltransferase: cDNA cloning and localization on chromosome 14q24.2-q24.3." Biochim Biophys Acta 1216(3);360-8. PMID: 8268217

Nakano94: Nakano K, Takase C, Sakamoto T, Nakagawa S, Inazawa J, Ohta S, Matuda S (1994). "Isolation, characterization and structural organization of the gene and pseudogene for the dihydrolipoamide succinyltransferase component of the human 2-oxoglutarate dehydrogenase complex." Eur J Biochem 224(1);179-89. PMID: 8076640

Nesbitt05: Nesbitt NM, Baleanu-Gogonea C, Cicchillo RM, Goodson K, Iwig DF, Broadwater JA, Haas JA, Fox BG, Booker SJ (2005). "Expression, purification, and physical characterization of Escherichia coli lipoyl(octanoyl)transferase." Protein Expr Purif 39(2);269-82. PMID: 15642479

Otulakowski87: Otulakowski G, Robinson BH (1987). "Isolation and sequence determination of cDNA clones for porcine and human lipoamide dehydrogenase. Homology to other disulfide oxidoreductases." J Biol Chem 262(36);17313-8. PMID: 3693355

Perham00: Perham RN (2000). "Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions." Annu Rev Biochem 69;961-1004. PMID: 10966480

Pons88: Pons G, Raefsky-Estrin C, Carothers DJ, Pepin RA, Javed AA, Jesse BW, Ganapathi MK, Samols D, Patel MS (1988). "Cloning and cDNA sequence of the dihydrolipoamide dehydrogenase component human alpha-ketoacid dehydrogenase complexes." Proc Natl Acad Sci U S A 85(5);1422-6. PMID: 3278312

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 19.0 on Mon Apr 27, 2015, biocyc11.