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Title 

Generation of human chiral metabolites of simvastatin and lovastatin by bacterial CYP102A1 mutants

Authors 

K H KimJ Y KangD H KimS H ParkDoo Il KimK D ParkY J LeeHeung Chae JungJae Gu PanT AhnC H Yun

Publisher 

American Society for Pharmacology and Experimental Therapeutics (ASPET)

Issue Date 

2011

Citation 

Drug Metabolism and Disposition, vol. 39, no. 1, pp. 140-150

Keywords 

3'' hydroxy lovastatin3'' hydroxy simvastatin6' beta hydroxy lovastatin6' beta hydroxy simvastatin6' beta hydroxymethyl simvastatin6' exomethylene simvastatin6' exothelyne lovastatincytochrome P450 BM3drug metabolitemevinolinsimvastatinunclassified drug

Abstract 

Recently, the wild-type and mutant forms of cytochrome P450 BM3 (CYP102A1) from Bacillus megaterium were found to oxidize various xenobiotic substrates, including pharmaceuticals, of human P450 enzymes. Simvastatin and lovastatin, which are used to treat hyperlipidemia and hypercholesterolemia, are oxidized by human CYP3A4/5 to produce several metabolites, including 6′β-hydroxy (OH), 3″-OH, and exomethylene products. In this report, we show that the oxidation of simvastatin and lovastatin was catalyzed by wild-type CYP102A1 and a set of its mutants, which were generated by site-directed and random mutagenesis. One major hydroxylated product (6′β-OH) and one minor product (6′-exomethylene), but not other products, were produced by CYP102A1 mutants. Formation of the metabolites was confirmed by highperformance liquid chromatography, liquid chromatography-mass spectroscopy, and NMR. Chemical methods to synthesize the metabolites of simvastatin and lovastatin have not been reported. These results demonstrate that CYP102A1 mutants can be used to produce human metabolites, especially chiral metabolites, of simvastatin and lovastatin. Our computational findings suggest that a conformational change in the cavity of the mutant active sites is related to the activity change. The modeling results also suggest that the activity change results from the movement of several specific residues in the active sites of the mutants. Furthermore, our computational findings suggest a correlation between the stabilization of the binding site and the catalytic efficiency of CYP102A1 mutants toward simvastatin and lovastatin.

ISSN 

0090-9556

Link 

http://dx.doi.org/10.1124/dmd.110.036392

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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