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

Permanent URL:
http://handle.nal.usda.gov/10113/23066
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.
Author(s):
Kobza, Keyna A. , Chaiseeda, Kittichai , Sarath, Gautam , Takacs, James M. , Zempleni, Janos
Subject(s):
histones , post-translational modification , benzoates , enzyme inhibitors , enzymes , enzyme activity , catalysts , epigenetics , gene expression regulation , DNA repair , chromatin , chemical structure , screening , application rate , enzyme kinetics , active transport , humans , blood plasma
Format:
p. 826-832.
Note:
Includes references
Source:
Journal of nutritional biochemistry 2008 Dec., v. 19, no. 12
Language:
English
Publisher:
New York, NY: Elsevier Science
Year:
2008
Collection:
Journal Articles, USDA Authors, Peer-Reviewed
File:
Download [PDF File]
Rights:
Works produced by employees of the U.S. Government as part of their official duties are not copyrighted within the U.S. The content of this document is not copyrighted.