Biotin-dependent carboxylases and related disorders: Comparative mechanisms and therapeutic advances

Biotin-dependent carboxylases (BDCs), including pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), and the ACC1/ACC2 isoforms of acetyl-CoA carboxylase (ACC), are core enzymes of intermediary metabolism. Inherited deficiencies of several BDCs, together with disorders of biotin utilization such as holocarboxylase synthetase and biotinidase deficiencies, produce a heterogeneous group of metabolic disorders, although the strength of human disease evidence differs markedly among individual enzymes. This review compares the domain architecture and shared two-site catalytic mechanism of these enzymes, including the biotin-carrying swinging arm. It then contrasts the clinical phenotypes and molecular mechanisms of the primary carboxylase deficiencies and the disorders of biotin utilization. Diagnostic approaches and current management are outlined, followed by a critical appraisal of emerging disease-modifying therapies, with propionic acidemia as the most extensively studied translational model spanning gene therapy, mRNA replacement, enzyme replacement, small-molecule candidates, and anaplerotic strategies. We conclude that a shared catalytic principle does not imply shared disease biology, and that treatment strategies must be matched to the metabolic context of each disorder.