Biotin Transport in the Rat Central Nervous System.

Lo, Warren; Kadlecek, Theresa A.; Packman, Seymour

doi:10.3177/jnsv.37.567

Cited by 11 publications

(9 citation statements)

References 18 publications

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“…Despite severe biotin deficiency, the level of biotinylated carboxylases in brain was similar to that of control animals, whereas liver was grossly deficient in carboxylase-biotin content. Previous studies had also shown that brain biotin content as well as the activity of biotin-dependent carboxylases are relatively preserved in the face of biotin starvation and systemic biotin deficiency in rats (35)(36)(37)(38)(39). The reduction in protein-bound biotin in liver was likely caused by a combination of a decrease in carboxylase levels because of reduced synthesis and impairment in carboxylase biotinylation because of reduced synthesis of HCS.…”

Section: Biotin Availability Regulates Mrna Levels Of the Biotin Utilmentioning

confidence: 98%

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

Pacheco‐Alvarez

Solorzano–Vargas

Gravel

et al. 2004

Journal of Biological Chemistry

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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 downregulation 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.

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Section: Biotin Availability Regulates Mrna Levels Of the Biotin Utilmentioning

confidence: 98%

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

Pacheco‐Alvarez

Solorzano–Vargas

Gravel

et al. 2004

Journal of Biological Chemistry

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“…Second, active carrier-mediated transport mechanisms raise biotin in CSF to levels 50 -250% greater than plasma, and maintain the activity of biotin-dependent enzymes in brain even during challenge with low dietary biotin (Bhagavan and Coursin, 1970;Chiang and Mistry, 1974;Sander et al, 1982;Mock, 1987, 1988;Lo et al, 1991). Third, biotinidase has specific activity in brain and has been localized to select cell types Hayakawa, 1989, 1990;Heller et al, 2002).…”

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confidence: 99%

Biotin is endogenously expressed in select regions of the rat central nervous system

McKay

Molineux

Turner

2004

J of Comparative Neurology

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The vitamin biotin is an endogenous molecule that acts as an important cofactor for several carboxylases in the citric acid cycle. Disorders of biotin metabolism produce neurological symptoms that range from ataxia to sensory loss, suggesting the presence of biotin in specific functional systems of the CNS. Although biotin has been described in some cells of nonmammalian nervous systems, the distribution of biotin in mammalian CNS is virtually unknown. We report the presence of biotin in select regions of rat CNS, as revealed with a monoclonal antibody directed against biotin and with avidin- and streptavidin-conjugated labels. Detectable levels of biotin were primarily found caudal to the diencephalon, with greatest expression in the cerebellar motor system and several brainstem auditory nuclei. Biotin was found as a somatic label in cerebellar Purkinje cells, in cell bodies and proximal dendrites of cerebellar deep nuclear neurons, and in red nuclear neurons. Biotin was detected in cells of the spiral ganglion, somata and proximal dendrites of cells in the cochlear nuclei, superior olivary nuclei, medial nucleus of the trapezoid body, and nucleus of the lateral lemniscus. Biotin was further found in pontine nuclei and fiber tracts, the substantia nigra pars reticulata, lateral mammillary nucleus, and a small number of hippocampal interneurons. Biotin was detected in glial cells of major tract systems throughout the brain but was most prominent in tracts of the hindbrain. Biotin is thus expressed in select regions of rat CNS with a distribution that correlates to the known clinical sequelae associated with biotin deficiencies.

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“…Because symptoms can be prevented or reversed with pharmacological doses of biotin and because some cases of biotinidase deficiency have been associated with progressive encephalopathy (40,41), it has been suggested that the biotin pathway is involved in these disorders. Yet the relationship to abnormalities in biotinidase, HCS, or even biotin transport has been elusive (36,37,42). It is possible that these disorders represent different degrees of the same disease in which the delicate balance between utilization of exogenous biotin and the recycling of the endogenous vitamin have been disrupted, affecting the expression of HCS and the biotin cycle.…”

Section: Discussionmentioning

confidence: 99%

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

Pérez-Monjaras

Cervantes-Roldán

Meneses-Morales

et al. 2008

Journal of Biological Chemistry

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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.

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Biotin Transport in the Rat Central Nervous System.

Cited by 11 publications

References 18 publications

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

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

Biotin is endogenously expressed in select regions of the rat central nervous system

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

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