Figure 1.

The leucine catabolism pathway. (Panel (A)) L-leucine is initially converted to α-ketoisocaproate in a reaction catalyzed by branched chain aminotransferase (BCAT) which employs α-ketoglutarate (α-KG) as amino group acceptor, yielding glutamate (Glu). α-Ketoisocaproate is then oxidatively decarboxylated by branched chain α-keto acid dehydrogenase (BCKDH) to form isovaleryl CoA. Subsequently, isovaleryl CoA dehydrogenase (IVD) oxidizes isovaleryl CoA to 3-methylcrotonyl CoA. This metabolite is then carboxylated to trans-3MGC CoA by 3-methylcrotonyl CoA carboxylase (3MCCCase). trans-3MGC CoA is then dehydrated by AUH to form (S)-HMG CoA which is cleaved by HMG CoA lyase (HMGCL), forming acetoacetate and acetyl CoA. (Panel (B)) Inborn errors of metabolism that lead to a deficiency in either AUH or HMGCL prevent complete catabolism of L-leucine, resulting in the excretion of organic acids, including trans-3MGC acid, cis-3MGC acid, 3-methylglutaric (3MG) acid, HMG acid (only in HMGCL deficiency) and 3-hydroxyisovaleric (3-HIV) acid.