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Research ArticleArticle

Human Cytochrome P450scc (CYP11A1) Catalyzes Epoxide Formation with Ergosterol

Robert C. Tuckey, Minh N. Nguyen, Jianjun Chen, Andrzej T. Slominski, Donna M. Baldisseri, Elaine W. Tieu, Jordan K. Zjawiony and Wei Li
Drug Metabolism and Disposition March 2012, 40 (3) 436-444; DOI: https://doi.org/10.1124/dmd.111.042515
Robert C. Tuckey
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Minh N. Nguyen
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Jianjun Chen
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Andrzej T. Slominski
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Donna M. Baldisseri
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Elaine W. Tieu
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Jordan K. Zjawiony
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Wei Li
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Abstract

Cytochrome P450scc (P450scc) catalyzes the cleavage of the side chain of both cholesterol and the vitamin D3 precursor, 7-dehydrocholesterol. The aim of this study was to test the ability of human P450scc to metabolize ergosterol, the vitamin D2 precursor, and define the structure of the major products. P450scc incorporated into the bilayer of phospholipid vesicles converted ergosterol to two major and four minor products with a kcat of 53 mol · min−1 · mol P450scc−1 and a Km of 0.18 mol ergosterol/mol phospholipid, similar to the values observed for cholesterol metabolism. The reaction of ergosterol with P450scc was scaled up to make enough of the two major products for structural analysis. From mass spectrometry, NMR, and comparison of the NMR data to that for similar molecules, we determined the structures of the two major products as 20-hydroxy-22,23-epoxy-22,23-dihydroergosterol and 22-keto-23-hydroxy-22,23-dihydroergosterol. Molecular modeling and nuclear Overhauser effect (or enhancement) spectroscopy spectra analysis helped to establish the configurations at C20, C22, and C23 and determine the final structures of major products as 22R,23S-epoxyergosta-5,7-diene-3β,20α-diol and 3β,23S-dihydroxyergosta-5,7-dien-22-one. It is likely that the formation of the second product is through a 22,23-epoxy (oxirane) intermediate followed by C22 hydroxylation with the formation of strained 22-hydroxy-22,23-epoxide (oxiranol), which is immediately transformed to the more stable α-hydroxyketone. Molecular modeling of ergosterol into the P450scc crystal structure positioned the ergosterol side chain consistent with formation of the above products. Thus, we have shown that P450scc efficiently catalyzes epoxide formation with ergosterol giving rise to novel epoxy, hydroxy, and keto derivatives, without causing cleavage of the side chain.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant R01-AR052190] (to A.T.S.); the University of Western Australia; and the College of Pharmacy at the University of Tennessee Health Science Center.

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

    http://dx.doi.org/10.1124/dmd.111.042515.

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

  • ABBREVIATIONS:

    P450scc
    cytochrome P450scc
    COSY
    correlation spectroscopy
    TOCSY
    total correlation spectroscopy
    NOESY
    nuclear Overhauser effect spectroscopy
    HSQC
    heteronuclear single quantum correlation spectroscopy
    HMBC
    heteronuclear multiple-bond correlation spectroscopy
    TLC
    thin-layer chromatography
    HPLC
    high-performance liquid chromatography
    NOE
    nuclear Overhauser effect.

  • Received August 25, 2011.
  • Accepted November 21, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

ERGOSTEROL METABOLISM BY HUMAN CYTOCHROME P450scc

Robert C. Tuckey, Minh N. Nguyen, Jianjun Chen, Andrzej T. Slominski, Donna M. Baldisseri, Elaine W. Tieu, Jordan K. Zjawiony and Wei Li
Drug Metabolism and Disposition March 1, 2012, 40 (3) 436-444; DOI: https://doi.org/10.1124/dmd.111.042515

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Research ArticleArticle

ERGOSTEROL METABOLISM BY HUMAN CYTOCHROME P450scc

Robert C. Tuckey, Minh N. Nguyen, Jianjun Chen, Andrzej T. Slominski, Donna M. Baldisseri, Elaine W. Tieu, Jordan K. Zjawiony and Wei Li
Drug Metabolism and Disposition March 1, 2012, 40 (3) 436-444; DOI: https://doi.org/10.1124/dmd.111.042515
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