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MetaCyc Pathway: 2-oxoisovalerate decarboxylation to isobutanoyl-CoA
Inferred from experiment

Enzyme View:

Pathway diagram: 2-oxoisovalerate decarboxylation to isobutanoyl-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-oxo acid dehydrogenase complex, branched-chain α-keto acid dehydrogenase complex

Superclasses: Generation of Precursor Metabolites and EnergyRespiration

Some taxa known to possess this pathway include : Geobacillus stearothermophilus, Homo sapiens, Mus musculus, Pseudomonas aeruginosa, Pseudomonas putida, Rattus norvegicus, Sulfolobus solfataricus, Synechocystis

Expected Taxonomic Range: Archaea, Bacteria , Eukaryota

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), the branched-chain α-keto acid dehydrogenase complex (BCDHC - this pathway), 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 3-methyl-2-oxobutanoate, a transamination product of L-valine, is used as an example for the 2-oxo acid substrate of the branched-chain dehydrogenase complex (BCDHC). This reaction is summarized by the EC entry

3-methyl-2-oxobutanoate + coenzyme A + NAD+ → isobutanoyl-CoA + CO2 + NADH.

BCDHC can also recognize 4-methyl-2-oxopentanoate and (S)-3-methyl-2-oxopentanoate (which are the transamination products of L-leucine and L-isoleucine, respectively), and plays a key role in the degradation of L-valine, L-leucine, and L-isoleucine.

Created 28-Nov-2005 by Caspi R, SRI International


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

Wang93a: Wang GF, Kuriki T, Roy KL, Kaneda T (1993). "The primary structure of branched-chain alpha-oxo acid dehydrogenase from Bacillus subtilis and its similarity to other alpha-oxo acid dehydrogenases." Eur J Biochem 213(3);1091-9. PMID: 8504804

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

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

AEvarsson00: AEvarsson A, Chuang JL, Wynn RM, Turley S, Chuang DT, Hol WG (2000). "Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease." Structure 8(3);277-91. PMID: 10745006

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

Chang02: Chang CF, Chou HT, Chuang JL, Chuang DT, Huang TH (2002). "Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex." J Biol Chem 277(18);15865-73. PMID: 11839747

Chang06: Chang CF, Chou HT, Lin YJ, Lee SJ, Chuang JL, Chuang DT, Huang TH (2006). "Structure of the subunit binding domain and dynamics of the di-domain region from the core of human branched chain alpha-ketoacid dehydrogenase complex." J Biol Chem 281(38);28345-53. PMID: 16861235

Chuang84: Chuang DT, Hu CC, Ku LS, Niu WL, Myers DE, Cox RP (1984). "Catalytic and structural properties of the dihydrolipoyl transacylase component of bovine branched-chain alpha-keto acid dehydrogenase." J Biol Chem 259(14);9277-84. PMID: 6746648

Chuang90: Chuang JL, Cox RP, Chuang DT (1990). "Molecular cloning of the mature E1b-beta subunit of human branched-chain alpha-keto acid dehydrogenase complex." FEBS Lett 262(2);305-9. PMID: 2335211

Chuang94: Chuang JL, Fisher CR, Cox RP, Chuang DT (1994). "Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex." Am J Hum Genet 55(2);297-304. PMID: 8037208

Chuang95: Chuang JL, Davie JR, Chinsky JM, Wynn RM, Cox RP, Chuang DT (1995). "Molecular and biochemical basis of intermediate maple syrup urine disease. Occurrence of homozygous G245R and F364C mutations at the E1 alpha locus of Hispanic-Mexican patients." J Clin Invest 95(3);954-63. PMID: 7883996

Chuang96: Chuang JL, Cox RP, Chuang DT (1996). "Maple syrup urine disease: the E1beta gene of human branched-chain alpha-ketoacid dehydrogenase complex has 11 rather than 10 exons, and the 3' UTR in one of the two E1beta mRNAs arises from intronic sequences." Am J Hum Genet 58(6);1373-7. PMID: 8651316

Danner89: Danner DJ, Litwer S, Herring WJ, Pruckler J (1989). "Construction and nucleotide sequence of a cDNA encoding the full-length preprotein for human branched chain acyltransferase." J Biol Chem 264(13);7742-6. PMID: 2708389

Dariush91: Dariush N, Fisher CW, Cox RP, Chuang DT (1991). "Structure of the gene encoding the entire mature E1 alpha subunit of human branched-chain alpha-keto acid dehydrogenase complex." FEBS Lett 284(1);34-8. PMID: 2060625

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

Fisher89: Fisher CW, Chuang JL, Griffin TA, Lau KS, Cox RP, Chuang DT (1989). "Molecular phenotypes in cultured maple syrup urine disease cells. Complete E1 alpha cDNA sequence and mRNA and subunit contents of the human branched chain alpha-keto acid dehydrogenase complex." J Biol Chem 264(6);3448-53. PMID: 2914958

Fisher91: Fisher CW, Lau KS, Fisher CR, Wynn RM, Cox RP, Chuang DT (1991). "A 17-bp insertion and a Phe215----Cys missense mutation in the dihydrolipoyl transacylase (E2) mRNA from a thiamine-responsive maple syrup urine disease patient WG-34." Biochem Biophys Res Commun 174(2);804-9. PMID: 1847055

Fisher91a: Fisher CR, Fisher CW, Chuang DT, Cox RP (1991). "Occurrence of a Tyr393----Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population." Am J Hum Genet 49(2);429-34. PMID: 1867199

Fisher91b: Fisher CR, Chuang JL, Cox RP, Fisher CW, Star RA, Chuang DT (1991). "Maple syrup urine disease in Mennonites. Evidence that the Y393N mutation in E1 alpha impedes assembly of the E1 component of branched-chain alpha-keto acid dehydrogenase complex." J Clin Invest 88(3);1034-7. PMID: 1885764

Harris97: Harris RA, Hawes JW, Popov KM, Zhao Y, Shimomura Y, Sato J, Jaskiewicz J, Hurley TD (1997). "Studies on the regulation of the mitochondrial alpha-ketoacid dehydrogenase complexes and their kinases." Adv Enzyme Regul 37;271-93. PMID: 9381974

Hummel88: Hummel KB, Litwer S, Bradford AP, Aitken A, Danner DJ, Yeaman SJ (1988). "Nucleotide sequence of a cDNA for branched chain acyltransferase with analysis of the deduced protein structure." J Biol Chem 263(13);6165-8. PMID: 3245861

Kim02: Kim H (2002). "Activity of human dihydrolipoamide dehydrogenase is reduced by mutation at threonine-44 of FAD-binding region to valine." J Biochem Mol Biol 35(4);437-41. PMID: 12297006

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

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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 Pathway Tools version 19.5 (software by SRI International) on Wed Jan 2, 2002, biocyc12.