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J. Biol. Chem., Vol. 279, Issue 50, 52312-52318, December 10, 2004

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Paradoxical Regulation of Biotin Utilization in Brain and Liver and Implications for Inherited Multiple Carboxylase Deficiency^*

Diana Pacheco-Alvarez||, R. Sergio Solórzano-Vargas||, Roy A. Gravel, Rafael Cervantes-Roldán, Antonio Velázquez¶, and Alfonso León-Del-Río**

From the Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México DF 04510, México, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N1, and ^¶Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México DF 04530, México

Holocarboxylase synthetase (HCS) catalyzes the biotinylation of five carboxylases in human cells, and mutations of HCS cause multiple carboxylase deficiency (MCD). Although HCS also participates in the regulation of its own mRNA levels, the relevance of this mechanism to normal metabolism or to the MCD phenotype is not known. In this study, we show that mRNA levels of enzymes involved in biotin utilization, including HCS, are down-regulated during biotin deficiency in liver while remaining constitutively expressed in brain. We propose that this mechanism of regulation is aimed at sparing the essential function of biotin in the brain at the expense of organs such as liver and kidney during biotin deprivation. In MCD, it is possible that some of the manifestations of the disease may be associated with down-regulation of biotin utilization in liver because of the impaired activity of HCS and that high dose biotin therapy may in part be important to overcoming the adverse regulatory impact in such organs.

Received for publication, June 23, 2004 , and in revised form, August 31, 2004.

^* This work was supported by Grant 40001-Q from the Consejo Nacional de Ciencia y Tecnología and Grant IN235202 from the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica from Universidad Nacional Autónoma de México. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| These authors contributed equally to this study. Recipients of scholarships from Consejo Nacional de Ciencia y Tecnología and Dirección General de Asuntos del Personal Académico-Universidad Nacional Autónoma de México.

^** To whom correspondence should be addressed: Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas. Universidad Nacional Autónoma de México, México D. F. 04510, México. Tel.: 525-622-3891; Fax: 525-622-3855; E-mail: leon{at}biomedicas.unam.mx.

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