Branched-chain amino acid (BCAA) catabolism — transamination and the BCKDH complex

The committed, shared initial steps of the catabolism of the three branched-chain amino acids (BCAAs: L-leucine, L-isoleucine, L-valine), operating in the mitochondrial matrix. Branched-chain aminotransferase (BCAT2, the mitochondrial isozyme; BCAT1 is cytosolic) first reversibly transaminates each BCAA with 2-oxoglutarate to the corresponding branched-chain 2-oxo (alpha-keto) acid (BCKA: alpha-ketoisocaproate from Leu, alpha-keto-beta- methylvalerate from Ile, alpha-ketoisovalerate from Val) plus L-glutamate. The branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex — a large mitochondrial multienzyme complex homologous to the pyruvate and 2-oxoglutarate dehydrogenase complexes — then catalyses the irreversible, rate-limiting, committed oxidative decarboxylation of the BCKAs to the corresponding branched-chain acyl-CoA thioesters + CO2 + NADH. The complex has three catalytic components: E1 (a thiamine-pyrophosphate-dependent decarboxylase, an alpha2-beta2 heterotetramer of BCKDHA/E1-alpha and BCKDHB/E1-beta) which decarboxylates the BCKA and reductively acylates the lipoyl arm; E2 (DBT, dihydrolipoyllysine-residue (2-methylpropanoyl)transferase) which forms the structural core and transfers the acyl group to CoA; and E3 (DLD, dihydrolipoyl dehydrogenase, an FAD flavoenzyme) which reoxidises the dihydrolipoyl arm and passes electrons to NAD+. E3/DLD is not BCKDH-specific: it is the common E3 shared with the pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and 2-oxoadipate dehydrogenase complexes and the glycine cleavage system. BCKDH flux is regulated by reversible phosphorylation of E1-alpha (inhibitory kinase BCKDK; activating phosphatase PPM1K). Inherited deficiency of BCKDHA, BCKDHB or DBT causes maple syrup urine disease (MSUD, from accumulation of BCAAs and their neurotoxic BCKAs); DLD deficiency causes a combined E3-deficiency phenotype (MSUD-like plus lactic acidosis / 2-oxoglutaric aciduria because PDH and OGDH are simultaneously impaired). Downstream, the branched-chain acyl-CoAs are degraded by substrate-specific dehydrogenases and hydratases (out of scope here) to acetyl-CoA, acetoacetate and/or succinyl-CoA (via propionyl-CoA/methylmalonyl-CoA for Ile and Val).