BCKDHB

BCKDHB is the gene that encodes the beta subunit of the branched-chain alpha-ketoacid dehydrogenase complex (BCKDH), a mitochondrial enzyme essential for the catabolism of branched-chain amino acids (valine, leucine, and isoleucine). The BCKDH complex catalyzes the oxidative decarboxylation of branched-chain alpha-keto acids, a key step in energy production from these amino acids. The E1 component of BCKDH is a heterotetramer composed of two alpha subunits and two beta subunits; the beta subunit is encoded by BCKDHB and works with the alpha subunit to form an active enzyme that requires thiamine pyrophosphate as a cofactor.

Regulation of BCKDH activity occurs through phosphorylation: the branched-chain ketoacid dehydrogenase kinase (BCKDK) phosphorylates and inhibits the complex, while the phosphatase PPM1K dephosphorylates and reactivates it. This regulation modulates flux through the branched-chain amino acid catabolic pathway in response to cellular needs.

Genetics and disease associations: Mutations in BCKDHB cause maple syrup urine disease (MSUD), a metabolic disorder inherited in an autosomal recessive pattern. BCKDHB-related MSUD is one form of the broader MSUD spectrum, characterized by accumulation of branched-chain amino acids and their keto acids, with potential neonatal metabolic crisis affecting the nervous system. Diagnosis is often made by newborn screening and confirmed by genetic testing.

Clinical management: Treatment focuses on dietary restriction of branched-chain amino acids and regular monitoring of amino acid levels. Some patients with specific mutations may respond to thiamine supplementation. In rare cases of severe disease, liver transplantation has been reported. Ongoing research seeks to clarify genotype-phenotype correlations and develop targeted therapies.