Branched-chain alpha-keto acid dehydrogenase complex
The branched-chain α-ketoacid dehydrogenase complex (BCKDC or BCKDH complex) is a multi-subunit complex of enzymes that is found on the inner membrane. This enzyme complex catalyzes the oxidative decarboxylation of branched, short-chain alpha-ketoacids. BCKDC is a member of the mitochondrial α-ketoacid dehydrogenase complex family comprising pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, key enzymes that function in the Krebs cycle.
This complex requires the following 5 coenzymes:
In animal tissue, BCKDC catalyzes an irreversible step in the catabolism of the branched-chain amino acids L-isoleucine, L-valine, and L-leucine, acting on their deaminated derivatives (L-alpha-keto-beta-methylvalerate, alpha-ketoisovalerate, and alpha-ketoisocaproate, respectively). In bacteria, this enzyme participates in the synthesis of branched, long-chain fatty acids. In plants, this enzyme is involved in the synthesis of branched, long-chain hydrocarbons.
The overall catabolic reaction catalyzed by the BCKDC is shown in Figure 1.
The mechanism of enzymatic catalysis by the BCKDC draws largely upon the elaborate structure of this large enzyme complex. This enzyme complex is composed of three catalytic components: alpha-ketoacid dehydrogenase (also referred to as the E1 component), dihydrolipoyl transacylase (E2 component), and dihydrolipoamide dehydrogenase (E3 component). In humans, 24 copies of E2 arranged in octahedral symmetry form the core of the BCKDC. Non-covalently linked to this polymer of 24 E2 subunits are 12 E1 α2β2 tetramers and 6 E3homodimers. In addition to the E1/E3-binding domain, there are 2 other important structural domains in the E2 subunit: (i) a lipoyl-bearing domain in the amino-terminal portion of the protein and (ii) an inner-core domain in the carboxy-terminal portion. The inner-core domain is linked to the other two domains of the E2 subunit by two interdomain segments (linkers). The inner-core domain is necessary to form the oligomeric core of the enzyme complex and catalyzes the acyltransferase reaction (shown in the "Mechanism" section below). The lipoyl domain of E2 is free to swing between the active sites of the E1, E2, and E3 subunits on the assembled BCKDC by virtue of the conformational flexibility of the aforementioned linkers (see Figure 2). Thus, in terms of function as well as structure, the E2 component plays a central role in the overall reaction catalyzed by the BCKDC.
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