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Title 

Oxidation of human cytochrome P450 1A2 substrates by Bacillus megaterium cytochrome P450 BM3

Authors 

D H KimK H KimDoo Il KimHeung Chae JungJae Gu PanY T ChiT AhnC H Yun

Publisher 

Elsevier

Issue Date 

2010

Citation 

Journal of Molecular Catalysis B:Enzymatic, vol. 63, no. 3, pp. 179-187

Keywords 

Drug metabolismHuman drug metabolitesHuman P450 1A2OxidationP450 BM3

Abstract 

Cytochrome P450 enzymes (P450s or CYPs) are good candidates for biocatalysis in the production of fine chemicals, including pharmaceuticals. Despite the potential use of mammalian P450s in various fields of biotechnology, these enzymes are not suitable as biocatalysts due to their low stability, low catalytic activity, and limited availability. Recently, wild-type and mutant forms of bacterial P450 BM3 (CYP102A1) from Bacillus megaterium have been found to metabolize various. It has therefore been suggested that CYP102A1 may be used to generate the metabolites of drugs and drug candidates. In this report, we show that the oxidation reactions of typical human CYP1A2 substrates (phenacetin, ethoxyresorufin, and methoxyresorufin) are catalyzed by both wild-type and mutant forms of CYP102A1. In the case of phenacetin, CYP102A1 enzymes show only O-deethylation product, even though two major products are produced as a result of O-deethylation and 3-hydroxylation reactions by human CYP1A2. Formation of the metabolites was confirmed by HPLC analysis and LC-MS to compare the metabolites with the actual biological metabolites produced by human CYP1A2. The results demonstrate that CYP102A1 mutants can be used for cost-effective and scalable production of human CYP1A2 drug metabolites. Our computational findings suggest that a conformational change in the cavity size of the active sites of the mutants is dependent on activity change. The modeling results further suggest that the activity change results from the movement of several specific residues in the active sites of the mutants.

ISSN 

1381-1177

Link 

http://dx.doi.org/10.1016/j.molcatb.2010.01.017

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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