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

The branched-chain amino acid aminotransferase (BCAT) and the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex are the two primary enzymatic components governing the catabolism of branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine [UniProt: P54687, P12694]. BCAT initiates the process by converting BCAAs into branched-chain alpha-keto acids (BCKAs), which are then irreversibly decarboxylated by the BCKDH complex, the rate-limiting step in the pathway [PubMed: 25158825]. Deficiencies in BCKDH activity lead to Maple Syrup Urine Disease (MSUD), characterized by the toxic accumulation of BCAAs and BCKAs, while overactivity or overexpression of BCAT1 is linked to metabolic reprogramming in aggressive cancers like glioblastoma [PubMed: 23792561]. Therapeutic interventions often target the regulatory kinase BCKDK to indirectly activate BCKDH in metabolic disorders, or aim to inhibit BCAT1 to starve cancer cells of nitrogen and energy sources [PubMed: 24415758]. Monitoring BCAA and BCKA levels in plasma serves as a critical biomarker for assessing the efficacy of these treatments [PubMed: 21356383]. Additionally, the regulation of these enzymes plays a significant role in systemic energy homeostasis and insulin sensitivity [PubMed: 22307346].

Other names

BCAT1BCAT2BCKDCBCAA catabolic pathwayBranched-chain keto acid dehydrogenaseBCAA transaminase

Pharmacological modulation involves the inhibition of BCAT to reduce BCAA transamination or the inhibition of BCKDK to prevent the phosphorylation-mediated inactivation of the BCKDH complex, thereby enhancing BCAA catabolic flux.