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J. Biol. Chem., Vol. 283, Issue 49, 34150-34158, December 5, 2008

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Impaired Biotinidase Activity Disrupts Holocarboxylase Synthetase Expression in Late Onset Multiple Carboxylase Deficiency^*

Anylu Pérez-Monjaras¹, Rafael Cervantes-Roldán, Iván Meneses-Morales¹, Roy A. Gravel, Sandra Reyes-Carmona, Sergio Solórzano-Vargas, Alfonso González-Noriega, and Alfonso León-Del-Río²

From the Departamento de Biología Molecular y Biotecnología, and Departamento de Biologia Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional AutónomadeMéxico, México D.F. 04510, México and the Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Biotinidase catalyzes the hydrolysis of the vitamin biotin from proteolytically degraded biotin-dependent carboxylases. This key reaction makes the biotin available for reutilization in the biotinylation of newly synthesized apocarboxylases. This latter reaction is catalyzed by holocarboxylase synthetase (HCS) via synthesis of 5'-biotinyl-AMP (B-AMP) from biotin and ATP, followed by transfer of the biotin to a specific lysine residue of the apocarboxylase substrate. In addition to carboxylase activation, B-AMP is also a key regulatory molecule in the transcription of genes encoding apocarboxylases and HCS itself. In humans, genetic deficiency of HCS or biotinidase results in the life-threatening disorder biotin-responsive multiple carboxylase deficiency, characterized by a reduction in the activities of all biotin-dependent carboxylases. Although the clinical manifestations of both disorders are similar, they differ in some unique neurological characteristics whose origin is not fully understood. In this study, we show that biotinidase deficiency not only reduces net carboxylase biotinylation, but it also impairs the expression of carboxylases and HCS by interfering with the B-AMP-dependent mechanism of transcription control. We propose that biotinidase-deficient patients may develop a secondary HCS deficiency disrupting the altruistic tissue-specific biotin allocation mechanism that protects brain metabolism during biotin starvation.

Received for publication, September 9, 2008

^* This work was supported by Consejo Nacional de Ciencia y Tecnología Grant 48862 and Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica Grant IN220206-3 and funds from the 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.

¹ Recipients of doctoral scholarships from the Consejo Nacional de Ciencia y Tecnología.

² To whom correspondence should be addressed: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, México D.F. 04510, México. Tel.: 5255-5622-8940; E-mail: leon{at}biomedicas.unam.mx.

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