Impaired biotinidase activity disrupts holocarboxylase synthetase expression in late onset multiple carboxylase deficiency.
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.
Pérez-Monjaras
Anylu
A
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional AutónomadeMéxico, México D.F. 04510, México.
Cervantes-Roldán
Rafael
R
Meneses-Morales
Iván
I
Gravel
Roy A
RA
Reyes-Carmona
Sandra
S
Solórzano-Vargas
Sergio
S
González-Noriega
Alfonso
A
León-Del-Río
Alfonso
A
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001710:Biotin / Q000737:chemistry / Q000502:physiology*; D043523:Biotinidase / Q000737:chemistry*; D028921:Biotinidase Deficiency / Q000201:enzymology* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000096:biosynthesis*; D018929:Cell Culture Techniques; D006152:Cyclic GMP / Q000737:chemistry; D028922:Holocarboxylase Synthetase Deficiency / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D014158:Transcription, Genetic
D001710:Biotin; D043523:Biotinidase; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases; D006152:Cyclic GMP