Branched-chain alpha-keto acid dehydrogenase complex (BCKDC) (BCKDC)

The branched-chain alpha-keto acid dehydrogenase complex (BCKDC) is a multi-subunit mitochondrial enzyme responsible for the rate-limiting step in the breakdown of branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine (UniProt P12694, P21953). It consists of three main components: E1 (a heterotetramer of alpha and beta subunits), E2 (dihydrolipoyl transacylase), and E3 (dihydrolipoamide dehydrogenase) (StatPearls, NBK470577). Deficiencies in the E1 subunits, encoded by the BCKDHA and BCKDHB genes, lead to Maple Syrup Urine Disease (MSUD), a condition characterized by the toxic accumulation of BCAAs and their corresponding alpha-keto acids (NCBI Gene ID 593, 594). Therapeutic strategies focusing on gene replacement involve using viral vectors, typically adeno-associated virus (AAV), to deliver functional BCKDHA or BCKDHB genes to the liver to restore enzyme activity and prevent neurotoxicity (PubMed PMC7053886). This approach aims to normalize metabolic flux and reduce the risk of metabolic crises in MSUD patients. Successful gene replacement would allow patients to tolerate a normal protein diet and eliminate the need for strict metabolic monitoring (PubMed PMC6453515).

Other names

BCKDH2-oxoisovalerate dehydrogenase complexBranched-chain keto acid dehydrogenaseBCKDH complexE1 component of BCKDCBCKDHABCKDHB

Gene replacement therapy delivers functional BCKDHA or BCKDHB cDNA to target cells to produce active E1 alpha or beta subunits, which assemble with endogenous subunits to form a functional BCKDC complex, restoring the oxidative decarboxylation of branched-chain amino acids (PubMed PMC7053886).