NDLI: Heterologous expression of CYP102A5 variant from Bacillus cereus CYPPB-1: Validation of model for predicting drug metabolism of human P450 probe substrates

Content Provider	Springer Nature Link
Author	Pendyala, Brahmaiah Chaganti, Subba Rao Thadikamala, Sathish Reddy Shetty, Prakasham
Copyright Year	2013
Abstract	CYP102A5 variant (ADL27534) from isolated Bacillus cereus CYPPB-1 was heterologously expressed in Escherichia coli Top 10 cells. Comparative sequence analysis of purified CYP102A5 variant with respect to reported CYP102A5 (AAP10153) from Bacillus cereus ATCC 14579 revealed amino acid sequence changes at positions P245S and M318I of heme domain. The binding affinities of 15 selected human P450 probe substrates towards isolated CYP102A5 were analyzed in silico using a homology model together with molecular docking techniques to predict the human drug metabolism. In vitro analysis suggested that the purified CYP102A5 metabolizes typical substrates of human CYP2C9, CYP2D6, CYP2E1, and CYP3A4, such as coumarin, propranolol, aniline, chlorzoxazone, p-nitrophenol, and nifedipine. The calculated K M values for propranolol, chloroxazone, coumarin, aniline, and 4-nitrophenol were calculated to be 0.962 ± 0.041, 1.254 ± 0.057, 2.859 ± 0.083, 2.732 ± 0.106, and 2.528 ± 0.11 mM, respectively. Importantly, taking a ChemScore cutoff value of −31 kJ/mol, substrate binding at active site and in vitro activity as the distinguishing lines between “substrates” and “nonsubstrates” revealed one false-positive and one false-negative results out of the 15 compounds examined. This is the first report on validation of CYP102A family homology model for in silico prediction of human drug metabolism.
Starting Page	8107
Ending Page	8119
Page Count	13
File Format	PDF
ISSN	01757598
Journal	Applied Microbiology and Biotechnology
Volume Number	97
Issue Number	18
e-ISSN	14320614
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2013-01-04
Publisher Place	Berlin, Heidelberg
Access Restriction	Subscribed
Subject Keyword	Bacillus cereus CYP102A5 Heterologous expression Homology modeling Docking studies Human P450 probe substrates Microbiology Microbial Genetics and Genomics Biotechnology
Content Type	Text
Resource Type	Article
Subject	Medicine Applied Microbiology and Biotechnology Biotechnology

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