page_title: Branched-chain alpha-keto acid dehydrogenase complex
section_title: Mechanism
hierarchical_section_title: Branched-chain alpha-keto acid dehydrogenase complex / Mechanism
caption_attribution_description: English: 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.
context_page_description: The branched-chain α-ketoacid dehydrogenase complex is a multi-subunit complex of enzymes that is found on the mitochondrial 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.
context_section_description: As previously mentioned, BCKDC’s primary function in mammals is to catalyze an irreversible step in the catabolism of branched-chain amino acids. However, the 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. The BCKDC will also oxidize pyruvate, but at such a slow rate this side reaction has very little physiological significance.
  The reaction mechanism is as follows. Please note that any of several branched-chain α-ketoacids could have been used as a starting material; for this example, α-ketoisovalerate was arbitrarily chosen as the BCKDC substrate.
  NOTE: Steps 1 and 2 occur in the E₁ domain
  STEP 1: α-ketoisovalerate combines with TPP and is then decarboxylated. The proper arrow-pushing mechanism is shown in Figure 3.
  STEP 2: 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. The proper arrow-pushing mechanism is shown in Figure 4.
  NOTE: The acylated lipoyl arm now leaves E₁ and swings into the E₂ active site, where Step 3 occurs.
  STEP 3: Acyl group transfer to CoA. The proper arrow-pushing mechanism is shown in Figure 5.
  *NOTE: The reduced lipoyl arm now swings into the E₃ active site, where Steps 4 and 5 occur.
  STEP 4: Oxidation of the lipoyl moiety by the FAD coenzyme, as shown in Figure 6.
  STEP 5: Reoxidation of FADH₂ to FAD, producing NADH:
  FADH₂ + NAD⁺ --> FAD + NADH + H⁺
caption: 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.
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