Branched-chain amino acid aminotransferase and branched-chain alpha-keto acid dehydrogenase complexes (BCAT and BCKDH)

The Branched-Chain Amino Acid Aminotransferase (BCAT) and Branched-Chain Alpha-Keto Acid Dehydrogenase (BCKDH) complexes are the primary enzymatic systems responsible for the catabolism of branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine. BCAT catalyzes the initial reversible transamination of BCAAs into branched-chain alpha-keto acids (BCKAs), while the BCKDH complex performs the subsequent irreversible oxidative decarboxylation, which serves as the rate-limiting step in the pathway. These enzymes are critical for maintaining BCAA homeostasis and regulating the mTOR signaling pathway, which influences protein synthesis and cell growth. Dysregulation of these complexes is linked to several major pathologies: BCAT1 is frequently overexpressed in various cancers to support metabolic reprogramming and tumor proliferation, whereas impaired BCKDH activity is associated with metabolic disorders such as obesity and type 2 diabetes, as well as the genetic disorder Maple Syrup Urine Disease (MSUD). Therapeutic strategies involve inhibiting BCAT1 to suppress tumor growth or activating the BCKDH complex (often by inhibiting its regulatory kinase, BCKDK) to lower elevated BCAA levels in metabolic and cardiovascular diseases.

Other names

Branched-chain amino acid catabolic machineryBCAA catabolic pathwayBCAT1/2 and BCKDCBranched-chain aminotransferase and branched-chain alpha-keto acid dehydrogenase

BCAT inhibition to reduce BCAA-derived glutamate and energy supply in cancer cells; BCKDK inhibition to prevent phosphorylation of the BCKDH E1 subunit, thereby activating the BCKDH complex to increase BCAA oxidation.