Impaired biotinidase activity disrupts holocarboxylase synthetase expression in late onset multiple carboxylase deficiency.

Abstract

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.

• Authors: Anylu Pérez-Monjaras, Rafael Cervantes-Roldán, Iván Meneses-Morales, Roy A Gravel, Sandra Reyes-Carmona, Sergio Solórzano-Vargas, Alfonso González-Noriega, Alfonso León-Del-Río
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 49 Pg. 34150-8 (Dec 05 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18845537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biotin
• Biotinidase
• Carbon-Nitrogen Ligases
• holocarboxylase synthetases
• Cyclic GMP

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Biotin (chemistry, physiology)
• Biotinidase (chemistry)
• Biotinidase Deficiency (enzymology, metabolism)
• Brain (metabolism)
• Carbon-Nitrogen Ligases (biosynthesis)
• Cell Culture Techniques
• Cyclic GMP (chemistry)
• Holocarboxylase Synthetase Deficiency (enzymology, genetics)
• Humans
• Models, Biological
• Molecular Sequence Data
• Transcription, Genetic