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Biotin (vitamin B7 or vitamin H) is a water-soluble vitamin that functions as a carboxyl carrier in carboxylation, decarboxylation, and transcarboxylation reactions, and is attached to a lysine residue in a highly conserved domain common to all biotin-dependent carboxylases. The 5 biotin-dependent carboxylases in humans are mitochondrial propionyl-coenzyme A (CoA), β-methylcrotonyl-CoA, pyruvate carboxylases, and mitochondrial and cytosolic forms of acetyl-CoA carboxylase, with each carboxylase having specific roles in fatty acid, glucose, and amino acid metabolism. Biotin is covalently attached to carboxylases by the enzyme holocarboxylase synthetase (HLCS) encoded by the HLCS gene, while biotinidase, encoded by the BTD gene, provides free biotin following proteolysis of the carboxylase protein. Hence, biotinidase deficiency (Mendelian Inheritance in Man [MIM] no. 253260) reflects an inability to hydrolyze biocytin (biotinyllysine) or small biotin-containing peptide fragments from carboxylases, leading to a lack of free biotin, while holocarboxylase synthetase deficiency (MIM no. 253270) reflects a failure to incorporate biotin into the apoenzymes. The activity of HLCS involves a 2-step, adenosine triphosphate (ATP)-dependent reaction in which biotin is first activated to biotinyl-5’-adenosine monophosphate (AMP) and then transferred to the apocarboxylase substrate, with release of AMP. Failure to attach or recycle biotin leads to significantly reduced activity of these biotin-dependent carboxylases and results in multiple carboxylase deficiency. Humans cannot synthesize biotin, and they obtain it from exogenous sources via intestinal absorption. Absorption of biotin and transport of the vitamin into a variety of cell types occurs via a saturable, Na+-dependent, carrier-mediated mechanism that involves the human sodium-dependent multivitamin transporter, hSMVT, encoded by the SLC5A6 gene, which has been shown to also transport pantothenate and lipoate.

More recently, HLCS has also been shown to have an additional role as a nuclear protein that may catalyze the binding of biotin to distinct lysine residues in chromatin proteins such as histones, although the specific mechanisms at play remain under debate. HLCS-dependent epigenetic marks are reported to be abundant in genomic regions that are subject to transcriptional repression. HLCS has been proposed to be a member of a multi-protein gene repression complex that directs its localization within chromatin. HLCS has also been linked to the regulation of histone deacetylases in a biotin-independent manner and to the regulation of heat shock proteins and inflammatory cytokines. Hence, HLCS appears to be a multifaceted protein involved in intermediary metabolism, as a transcriptional repressor, and in gene regulation of biotin-dependent and independent pathways.


Deficiencies of biotinidase and HLCS are autosomal recessive disorders with considerable clinical variability. Newborn screening for biotinidase deficiency has been carried out since the 1980s using direct enzyme testing. HLCS deficiency is screened for by tandem mass spectroscopy using elevated propionylcarnitine (C3) and hydroxypentanoylcarnitine (C5-OH) on dried blood spots. The urine organic acid profile may demonstrate elevated lactic, 3-OH isovaleric, 3-OH propionic, 3-methylcrotonyl, methylcitric, and tiglylglycine consistent with loss of function of the above carboxylases.


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