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:||Degradation/Utilization/Assimilation → Amino Acids Degradation|
|Generation of Precursor Metabolites and Energy → Respiration|
Some taxa known to possess this pathway include : Geobacillus stearothermophilus , Homo sapiens , Mus musculus , Pseudomonas aeruginosa , Pseudomonas putida , Rattus norvegicus , Sulfolobus solfataricus , Synechocystis
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 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 [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 126.96.36.199
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.
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
Wang93c: 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
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
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
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
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
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