Branched-chain alpha-keto acid dehydrogenase complex

In animal tissue, BCKDC catalyzes an irreversible step[2] 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) and converting them[3] to α-Methylbutyryl-CoA, Isobutyryl-CoA and Isovaleryl-CoA respectively.

This enzyme complex is composed of three catalytic components: In humans, 24 copies of E2 arranged in octahedral symmetry form the core of the BCKDC.

[9] 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).

[10] 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).

E1 catalyzes both the decarboxylation of the α-ketoacid and the subsequent reductive acylation of the lipoyl moiety (another catalytic cofactor) that is covalently bound to E2.

[14] The E3 component is a flavoprotein, and it re-oxidizes the reduced lipoyl sulfur residues of E2 using FAD (a catalytic cofactor) as the oxidant.

As previously mentioned, BCKDC's primary function in mammals is to catalyze an irreversible step in the catabolism of branched-chain amino acids.

However BCKDC has a relatively broad specificity, also oxidizing 4-methylthio-2-oxobutyrate and 2-oxobutyrate at comparable rates and with similar Km values as for its branched-chain amino acid substrates.

Figure 1: This is the overall reaction catalyzed by the branched-chain alpha-ketoacid dehydrogenase complex.
Figure 2: This is a schematic of the "swinging" lipoyl domain. Note that this lipoyl domain is covalently attached to the E 2 subunit of the BCKDC, but is free to swing between the E 1 , E 2 , and E 3 subunits. As is described in the "Mechanism" section, the ability of the lipoyl group to freely swing between the active sites on each of the three subunits of the BCKDC plays a large and important role in the catalytic activity of this enzyme complex. [ 13 ]
Figure 3: α-ketoisovalerate combines with TPP and is then decarboxylated
Figure 4: The 2-methylpropanol-TPP is oxidized to form an acyl group while being simultaneously transferred to the lipoyl cofactor on E2. Note that TPP is regenerated.
Figure 5: Acyl group transfer to CoA
Figure 6: Oxidation of the lipoyl moiety by the FAD coenzyme.