Exogenous (dietary) BCAAs are major precursors for protein synthesis, but are also used as an endogenous, alternative energy source during muscle protein catabolism. The initial step in LEU, VAL, and ILE catabolism is a reversible transamination step (reaction 1 in Fig 1) to form the BCKAs: α-ketoisocaproic acid, α-keto-3-methylvaleric acid and α-ketoisovaleric acid. 

The second step (reaction 2 in Fig 1) is an irreversible oxidative decarboxylation step catalyzed by the BCKD complex. The complex is present within the inner mitochondrial membrane. It is a multi-enzyme macromolecule with three catalytic components (E1α and E1β, E2, E3) and two regulatory enzymes (a kinase and a phosphatase). The subunits require NAD and TPP. The products of the reaction are the organic acid CoA intermediates: isovaleryl CoA, methylbutyryl CoA and isobutyryl CoA. In the absence of sufficient BCKD catalytic activity there is an accumulation of both the BCKAs and the BCAAs.

Figure 2: BCAA Catabolism by BCKD

Goals of medical nutrition therapy in MSUD are:

• Rapidly reduce toxic metabolites by restricting dietary BCAA to amounts allowing patients to achieve and maintain appropriate plasma BCAA amino acid concentrations
• Reduce catabolism
• Promote anabolism
• Monitor nutritional status and alter intake to promote normal growth, development and health maintenance
• Evaluate thiamin responsiveness if patient has residual BCKD activity; supplement if responsive