Biotinidase deficiency: A novel vitamin recycling defect

Wolf, Barry; Grier, Robert E.; McVoy, Julie R. Secor; Heard, Gregory S.

doi:10.1007/bf01800660

Cited by 135 publications

(55 citation statements)

References 33 publications

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“…4 In mammals, biotin reutilization occurs through the action of biotinidase, an enzyme which hydrolyzes biotin from biotinyl-lysine (biocytin) or short peptides containing biotin which are the products of normal proteolytic digestion of holocarboxylases. 8 In recent years, biotin has been described in the nucleus of cells, 9 including in tumor material [10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Nonenzymatic biotinylation of histone H2A

et al. 2009

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Holocarboxylase synthetase (HCS, eukaryotic enzyme) and BirA (prokaryotic) are biotin protein ligases that catalyze the ATP-dependent attachment of biotin to apocarboxylases via the reactive intermediate, bio-5 0 -AMP. In this study, we examined the in vitro mechanism of biotin attachment to histone H2A in the presence of HCS and BirA. The experiment derives from our observations that HCS is found in the nucleus of cells in addition to the cytoplasm, and it has the ability to attach biotin to histones in vitro (Narang et al., Hum Mol Genet 2004; 13:15-23). Using recombinant HCS or BirA, the rate of biotin attachment was considerably slower with histone H2A than with the biotin binding domain of an apocarboxylase. However, on incubation of recombinant H2A with chemically synthesized bio-5 0 -AMP, H2A was observed to be rapidly labeled with biotin in the absence of enzyme. Nonenzymatic biotinylation of a truncated apocarboxylase (BCCP87) has been previously reported (Streaker and Beckett, Protein Sci 2006; 15:1928-1935), though at a much slower rate than we observe for H2A. The specific attachment sites of nonenzymatically biotinylated recombinant H2A at different time points were identified using mass spectrometry, and were found to consist of a similar pattern of biotin attachment as seen in the presence of HCS, with preference for lysines in the highly basic N-terminal region of the histone. None of the lysine sites within H2A resembles the biotin attachment consensus sequence seen in carboxylases, suggesting a novel mechanism for histone biotinylation.

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Section: Introductionmentioning

confidence: 99%

Nonenzymatic biotinylation of histone H2A

et al. 2009

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“…Loss of HCS or biotinidase activity produces the neonatal or juvenile forms, respectively, of the disease multiple carboxylase deficiency (MCD) (1,11,12). Both forms of MCD are potentially fatal.…”

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confidence: 99%

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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“…HCS is a cytoplasmic, mitochondrial, and nuclear protein [1][2][3], whereas BTD is predominantly secreted into serum [4,5] but can also be found in the cell nucleus [2,4]. HCS catalyzes the covalent binding of biotin to a specific lysine residue in apocarboxylases to produce holocarboxylases [6].…”

Section: Introductionmentioning

confidence: 99%

Biotinyl-methyl 4-(amidomethyl)benzoate is a competitive inhibitor of human biotinidase

Kobza¹,

Chaiseeda²,

Sarath³

et al. 2008

The Journal of Nutritional Biochemistry

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M.; and Zempleni, Janos, "Biotinyl-methyl 4-(amidomethyl)benzoate is a competitive inhibitor of human biotinidase" (2008 Abstract Posttranslational modification of histones by biotinylation can be catalyzed by both biotinidase (BTD) and holocarboxylase synthetase. Biotinylation of histones is an important epigenetic mechanism to regulate gene expression, DNA repair, and chromatin remodeling. The role of BTD in histone biotinylation is somewhat ambiguous, given that BTD also catalyzes removal of the biotin tag from histones. Here, we sought to develop BTD inhibitors for future studies of the role of BTD in altering chromatin structure. We adopted an existing colorimetric BTD assay for use in a novel 96-well plate format to permit high-throughput screening of potential inhibitors. Biotin analogs were chemically synthesized and tested for their ability to inhibit human BTD. Seven of these compounds inhibited BTD by 26-80%. Biotinyl-methyl 4-(amidomethyl)benzoate had the largest effect on BTD, causing an 80% inhibition at 1 mM concentration. Enzyme kinetics studies were conducted to determine V max , K m and K i for the seven inhibitors; kinetics were consistent with the hypothesis that biotinyl-methyl 4-(amidomethyl)benzoate and the other compounds acted by competitive inhibition of BTD. Finally, biotinyl-methyl 4-(amidomethyl) benzoate did not affect biotin transport in human cells, suggesting specificity in regard to biotin-related processes.

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Biotinidase deficiency: A novel vitamin recycling defect

Cited by 135 publications

References 33 publications

Nonenzymatic biotinylation of histone H2A

Nonenzymatic biotinylation of histone H2A

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

Biotinyl-methyl 4-(amidomethyl)benzoate is a competitive inhibitor of human biotinidase

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