Reactome | BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV

BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV

Stable Identifier

R-HSA-9859138

Type

Pathway

Species

Homo sapiens

Compartment

mitochondrial matrix

Synonyms

a-ketoisocaproate, a-keto b-methylvalerate, or a-ketoisovalerate + CoA + NAD+ => isovaleryl-CoA, a-methylbutyryl-CoA, or isobuyryl-CoA + CO2 + NADH + H+, Oxidative decarboxylation of branched-chain alpha-keto acids

ReviewStatus

5/5

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BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV

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The mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex catalyzes the reactions of alpha-ketoisocaproate, alpha-keto beta-methylvalerate, or alpha-ketoisovalerate with CoA and NAD+ to form isovaleryl-CoA, alpha-methylbutyryl-CoA, or isobutyryl-CoA, respectively, and CO2 and NADH (Chuang and Shih, 2001). While bovine and microbial BCKD complexes have been characterized most extensively (Reed and Hackert 1990), structural studies of individual components and subcomplexes of human BCKD have confirmed their structures and roles in the overall oxidative decarboxylation process and have related these features to the disruptive effects of mutations on branched-chain amino acid metabolism in vivo: E1a and E1b components (AEvarsson et al., 2000), E2 (Chang et al., 2002), and E3 (DLD) (Brautigam et al., 2005). In addition, structural studies have confirmed the lipoylation of lysine residue 105 in E2 protein (Chang et al., 2002) and the loss of an aminoterminal mitochondrial transport sequence from mature E3 protein (Brautigam et al., 2005). Loss of mitochondrial transport sequences from proteins E1a, E1b, and E2 has been demonstrated by sequence analysis (Wynn et al., 1999). Defects in E1a, E1b, and E2 may cause so-called maple syrup urine disease, with accumulation of the abovementioned amino acids and their corresponding keto acids, leading to encephalopathy and progressive neurodegeneration (MSUD, MIM:248600; reviewed in Xu et al., 2020). Defects in the E3 (DLD) subunit, shared with other ketoacid dehydrogenase complexes, typically present as neonatal lactic acidosis due to lack of pyruvate dehydrogenase activity although symptoms of BCKDH deficiency may also be present.

Literature References

PubMed ID	Title	Journal	Year
2188967	Structure-function relationships in dihydrolipoamide acyltransferases. Reed, LJ, Hackert, ML	J Biol Chem	1990
33050626	Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders Xu, J, Ahrens-Nicklas, RC, Jakher, Y	Int J Mol Sci	2020
	The Metabolic and Molecular Bases of Inherited Disease, 8th ed Beaudet, AL, Scriver, CR, Sly, WS, Valle, D		2001
15946682	Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations Tomchick, DR, Machius, M, Chuang, DT, Chuang, JL, Brautigam, CA	J Mol Biol	2005
10745006	Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Hol, WG, Turley, S, Chuang, DT, Chuang, JL, Wynn, RM, Aevarsson, A	Structure Fold Des	2000
11839747	Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex Chuang, DT, Chou, HT, Chuang, JL, Chang, CF, Huang, TH	J Biol Chem	2002
7918575	Differential processing of human and rat E1 alpha precursors of the branched-chain alpha-keto acid dehydrogenase complex caused by an N-terminal proline in the rat sequence Chuang, DT, Wynn, RM, Kochi, H, Cox, RP	Biochim Biophys Acta	1994