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

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

doi:10.1074/jbc.m806985200

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.

Highlights

Because of the importance of biotin in cell metabolism, higher organisms face a constant threat to their survival because they are incapable of synthesizing the vitamin
In the presence of biotin, the HCSsGC-PKG pathway induces the expression of the components of the biotin cycle required for its transport and utilization: the sodium-dependent multivitamin transporter, PC, PCC, MCC, ACC, and holocarboxylase synthetase (HCS) [3, 5, 13]
This would seem to that distinguish this disorder from HCS deficiency, especially in be contrary to the need for scavenging biotin during limited relation to neurological presentation, are not fully understood supply, we showed that this pattern of gene repression is an [22]

Summary

Introduction

Because of the importance of biotin in cell metabolism, higher organisms face a constant threat to their survival because they are incapable of synthesizing the vitamin. Effect of Biotin Deficiency and Supplementation on Carboxylase Protein Levels in Normal and Biotinidase-deficient Cells— We explored the relationship between the lack of response to biotin stimulation observed in MCD-BD cells and the size of the pool of apocarboxylases available for biotinylation.

Results

Conclusion