Holocarboxylase synthetase (HLCS)

Holocarboxylase synthetase (HLCS) is an essential enzyme that catalyzes the covalent attachment of biotin (vitamin B7) to the lysine residues of specific apo-carboxylases, thereby activating them for roles in key metabolic processes, including gluconeogenesis, fatty acid synthesis, and branched-chain amino acid catabolism[1][2][4]. HLCS is also a chromatin-associated biotin ligase that attaches biotin to specific lysine residues of core histones (notably H3 and H4), participating in epigenetic regulation by repressing the expression of certain genes and maintaining genomic stability through the repression of retrotransposons[1][3][4]. Mutations in the HLCS gene underlie holocarboxylase synthetase deficiency, a rare but life-threatening inborn error of metabolism manifesting as multiple carboxylase deficiency for which biotin supplementation is the cornerstone of therapy[1][2]. There are currently no clinically approved HLCS inhibitors; biotin is both a physiological substrate and the therapeutic agent for deficiency. HLCS's central role in both intermediary metabolism and chromatin modification links metabolic and epigenetic regulation in human cells.

Other names

Biotin–protein ligaseBiotin apo-protein ligaseBiotin–[acetyl-CoA-carboxylase] ligaseBiotin–[methylcrotonoyl-CoA-carboxylase] ligaseBiotin–[methylmalonyl-CoA-carboxytransferase] ligaseBiotin–[propionyl-CoA-carboxylase (ATP-hydrolyzing)] ligaseHCSBiotin-protein ligaseHolocarboxylase synthetase (biotin–(propionyl-CoA-carboxylase (ATP-hydrolysing)) ligase)

Biotin supplementation compensates for the deficiency caused by mutations in HLCS, restoring biotinylation of carboxylases and histones