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Archives of Medical Research 33 (2002) 439–447


Biotin in Metabolism and Its Relationship to Human Disease
Diana Pacheco-Alvarez, R. Sergio Solórzano-Vargas and Alfonso León Del Río
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas (IIBM), Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico Received for publicationJanuary 2, 2002; accepted April 17, 2002 (02/001).

Biotin, a water-soluble vitamin, is used as cofactor of enzymes involved in carboxylation reactions. In humans, there are five biotin-dependent carboxylases: propionyl-CoA carboxylase; methylcrotonyl-CoA carboxylase; pyruvate carboxylase, and two forms of acetylCoA carboxylase. These enzymes catalyze key reactions in gluconeogenesis, fatty acidmetabolism, and amino acid catabolism; thus, biotin plays an essential role in maintaining metabolic homeostasis. In recent years, biotin has been associated with several diseases in humans. Some are related to enzyme deficiencies involved in biotin metabolism. However, not all biotin-responsive disorders can be explained based on the classical role of the vitamin in cell metabolism. Several groupshave suggested that biotin may be involved in regulating transcription or protein expression of different proteins. Biotinylation of histones and triggering of transduction signaling cascades have been suggested as underlying mechanisms behind these non-classical biotin-deficiency manifestation in humans. © 2002 IMSS. Published by Elsevier Science Inc.
Key Words: Biotin, Holocarboxylasesynthetase, Biotin deficiency, Multiple carboxylase deficiency.

Introduction Biotin is a water-soluble vitamin found in all organisms that functions as cofactor of enzymes known as biotin-dependent carboxylases (1). The role of biotin in carboxylases is to act as vector for carboxyl-group transfer between donor and acceptor molecules during carboxylation reaction. Covalent addition of biotin to theseproteins is catalyzed by biotin ligases, which in prokaryotes are known as BirA protein (2,3) and in eukaryotes as holocarboxylase synthetase (HCS) (1). For both BirA and HCS, biotin addition occurs as an ATPdependent, two-step reaction that, in the first step, involves synthesis of the intermediate, biotinyl-5 -AMP (B-AMP) (4,5). In the second step, B-AMP is substrate for transfer biotin, withrelease of AMP to a specific lysine residue in a highly conserved region in apocarboxylases (6–10). Until very recently, the sole known function of biotin in human cells was to act as cofactor of five biotin-dependent

Address reprint requests to: Dr. Alfonso León Del Río, Departamento de Biología Molecular y Biotecnología, IIBM, UNAM, CU, 04510 México, D.F., México. Tel.: ( 52) (55) 5622-3891;FAX: ( 52) (55) 56223855; E-mail:

carboxylases, including propionyl-CoA carboxylase (PCC), pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), acetyl-CoA carboxylase 1 (ACC-1), and acetylCoA carboxylase 2 (ACC-2) (11–13). These enzymes, discussed later, catalyze key reactions in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Because theseenzymes play such an important role in intermediary metabolism, biotin starvation or deficiencies of one enzyme involved in biotin utilization is potentially lethal. It has been suggested in recent years that biotin may play a role in other cellular events in eukaryotic organisms such as transcriptional or translational regulation or activity enhancement of different hepatic enzymes (14–23).Furthermore, biotin deficiency has been proven teratogenic in different animal species and the cause of several neurologic diseases (24– 26). Mechanisms involved in these other functions of biotin are largely unknown; however, it is possible that biotin may have been selected during evolution to play different roles in metabolism and gene expression of higher organisms. In this report, we review the...
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