Potential Role for Biotin in Gene Expression

In 1995, Hymes and Wolf discovered that biotini-dase can act as a biotinyl-transferase; biocytin serves as the source of biotin, and histones are specifically biotinylated. Approximately 25% of total cellular biotinidase activity occurs in the nucleus. Zempleni and coworkers demonstrated that the abundance of biotinylated histones varies with the cell cycle, that biotinylated histones are increased approximately twofold compared to quiescent lymphocytes, and that histones are debiotinylated enzymatically in a process that is at least partially catalyzed by biotini-dase. These observations suggest that biotin plays a role in regulating DNA transcription and regulation.

Although the mechanisms remain to be elucidated, biotin status has been shown to clearly effect gene expression. Cell culture studies suggest that cell proliferation generates an increased demand for biotin, perhaps mediated by increased synthesis of biotin-dependent carboxylases. Solozano-Vargas and cowor-kers reported that biotin deficiency reduces messenger RNA levels of holocarboxylase synthetase, a-ACC, and PCC and postulated that a cyclic GMP-dependent signaling pathway is involved in the pathogenesis.

Studies have been conducted on diabetic humans and rats that support an effect of biotin status on carbohydrate metabolism. Genes studied include glu-cokinase, phosphoenolpyruvate carboxykinase (PEPCK), and expression of the asialoglycoprotein receptor on the surface of hepatocytes. The effect of biotin status on PEPCK expression was particularly striking when diabetic rats were compared to nondia-betic rats. However, most studies have been performed on rats in which metabolic pathways have been perturbed prior to administration of biotin. Thus, the role of biotin in regulation of these genes during normal biotin status remains to be elucidated.

Hyperammonemia is a finding in biotin deficiency. Maeda and colleges have reported that ornithine transcarbamoylase (an enzyme in the urea cycle) is significantly reduced in biotin-deficient rats.

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