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Research ArticleArticle

Generation of Human Chiral Metabolites of Simvastatin and Lovastatin by Bacterial CYP102A1 Mutants

Keon-Hee Kim, Ji-Yeon Kang, Dong-Hyun Kim, Sun-Ha Park, Seon Ha Park, Dooil Kim, Ki Deok Park, Young Ju Lee, Heung-Chae Jung, Jae-Gu Pan, Taeho Ahn and Chul-Ho Yun
Drug Metabolism and Disposition January 2011, 39 (1) 140-150; DOI: https://doi.org/10.1124/dmd.110.036392
Keon-Hee Kim
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Ji-Yeon Kang
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Dong-Hyun Kim
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Sun-Ha Park
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Seon Ha Park
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Dooil Kim
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Ki Deok Park
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Young Ju Lee
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Heung-Chae Jung
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Jae-Gu Pan
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Taeho Ahn
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Chul-Ho Yun
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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 high-performance 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.

Footnotes

  • This work was supported in part by the 21C Frontier Microbial Genomics and the Application Center Program of the Ministry of Education, Science and Technology of the Republic of Korea; the National Research Foundation [Grant 2010-0027685]; the Second Stage BK21 Project from the Ministry of Education, Science and Technology of the Republic of Korea; and the Support Program for the Advancement of National Research Facilities and Equipment of the Ministry of Education, Science and Technology of the Republic of Korea (2010).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.036392.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    OH
    hydroxy
    FDA
    U.S. Food and Drug Administration
    MIST
    metabolites in safety testing
    WT
    wild type
    P450
    cytochrome P450
    CYP102A1
    cytochrome P450 BM3
    HPLC
    high-performance liquid chromatography
    LC
    liquid chromatography
    MS
    mass spectrometry
    αNF
    7,8-benzoflavone
    LOV
    lovastatin
    SIM
    simvastatin
    ESP
    electrostatic potential
    MM
    molecular mechanics
    PBSA
    Poisson Boltzmann and surface area
    MD
    molecular dynamics.

  • Received September 17, 2010.
  • Accepted October 20, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

Generation of Human Chiral Metabolites of Simvastatin and Lovastatin by Bacterial CYP102A1 Mutants

Keon-Hee Kim, Ji-Yeon Kang, Dong-Hyun Kim, Sun-Ha Park, Seon Ha Park, Dooil Kim, Ki Deok Park, Young Ju Lee, Heung-Chae Jung, Jae-Gu Pan, Taeho Ahn and Chul-Ho Yun
Drug Metabolism and Disposition January 1, 2011, 39 (1) 140-150; DOI: https://doi.org/10.1124/dmd.110.036392

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Research ArticleArticle

Generation of Human Chiral Metabolites of Simvastatin and Lovastatin by Bacterial CYP102A1 Mutants

Keon-Hee Kim, Ji-Yeon Kang, Dong-Hyun Kim, Sun-Ha Park, Seon Ha Park, Dooil Kim, Ki Deok Park, Young Ju Lee, Heung-Chae Jung, Jae-Gu Pan, Taeho Ahn and Chul-Ho Yun
Drug Metabolism and Disposition January 1, 2011, 39 (1) 140-150; DOI: https://doi.org/10.1124/dmd.110.036392
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