Topical Review Article Biological Effects of Pharmacological Concentrations of Biotin Cristina Fernandez-Mejia, PhD 1 , and Maria-Luisa Lazo-de-la-Vega-Monroy, PhD 1 Abstract Understanding the molecular mechanisms of vitamins has opened new perspectives regarding the relationship between nutritional signals and biological functions, which, in turn, has led to the development of new therapeutic agents. Although little is known about water-soluble vitamins as genetic modulators, evidence about their effects on gene expression has grown. In the case of biotin, besides its role as a carboxylase prosthetic group, it also affects gene expression and has a wide repertoire of effects on biological functions. Only recently, the role of pharmacological concentrations of biotin on systemic functions has attracted attention, and it is now being reconsidered with the help of new technologies. This novel approach could lead to new perspectives in its use as a therapeutic agent. The present review is focused on the effects of pharmacological concentrations of biotin on sev- eral biological functions and on the biotin signaling pathways that participate in gene expression. Keywords Biotin, coenzyme A, acetyl-CoA, propionyl-CoA, guanylate cyclase, protein kinase G, asialoglycoprotein, carboxylase, vitamin B group, pharmacological concentrations of biotin Received October 16, 2010. Accepted for publication October 16, 2010. In the last few decades, an increasing number of vitamin-mediated effects on gene expression have been discov- ered 1-3 in addition to their well-known roles as substrates and cofactors. 4 Examples are the lipophilic vitamins A and D, which serve as ligand precursors of the hormone nuclear receptors superfamily and thus affect systemic functions. 1,2 Extensive research on these vitamins has revealed the broad spectrum of actions in which they participate and has led to the development of new therapeutic agents against numerous diseases. 5-7 Although little is known about water-soluble vitamins as genetic modulators, there are many examples of their effects on gene expression. 8-11 Biotin is a water-soluble vitamin that acts as a prosthetic group of carboxylases. Unrelated to this classic role as a car- boxylase prosthetic group, pharmacological concentrations of biotin affect gene expression at both the transcriptional and the translational levels 9,10 and have a wide repertoire of effects on systemic processes such as development, 12 reproduction, 13-15 and metabolism. 16,17 This article will focus on the multiple actions of biotin at pharmacological concentrations. Biotin Functions as a Carboxylase Prosthetic Group Biotin is an essential nutrient, which plays a central role in intermediary metabolism, where it acts as a carboxyl carrier in carboxylation reactions. 18 Five biotin-dependent carboxylases have been recognized in mammals: acetyl- coenzyme A (CoA)-carboxylase-1 and -2, pyruvate carboxylase, propionyl-CoA carboxylase, and b-methylcrotonyl-CoA carbox- ylase. These enzymes act by transferring a carbonyl group from bicarbonate to metabolic intermediates. In carboxylases, biotin is attached to the e-amino group of lysine by the action of holocarboxylase synthetase in a two-step adenosine triphosphate (ATP)-dependent reaction, generating biotinyl-5 0 -adenosine monophosphate as an intermediate. In the second step, the biotinyl group is transferred to carboxylase apoenzymes forming a semipeptidic bond with lysine, located within the sequence Ala-Met-Lys-Met, which is highly conserved in apocarboxylases. 19 The biotin-dependent carboxylases participate in different metabolic pathways: acetyl-CoA carboxylase1, the only mam- malian carboxylase located in the cytoplasm, catalyzes the binding of bicarbonate to acetyl-CoA, which generates malonyl-CoA for fatty acid synthesis, whereas other carboxy- lases are located in the mitochondrial matrix; propionyl-CoA 1 Universidad Nacional Auto ´noma de Me ´xico, Mexico City, Mexico Corresponding Author: Cristina Fernandez-Mejia, PhD, Av. del Iman #1, 4 piso, Mexico City, CP 04530 Mexico Email: [email protected] Journal of Evidence-Based Complementary & Alternative Medicine 16(1) 40-48 ª The Author(s) 2011 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1533210110392947 http://cam.sagepub.com
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