Journal article

Mechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1)

Alexandr N Simonov, Jessica K Holien, Joyee Chun In Yeung, Ann D Nguyen, C Jo Corbin, Jie Zheng, Vladimir L Kuznetsov, Richard J Auchus, Alan J Conley, Alan M Bond, Michael W Parker, Raymond J Rodgers, Lisandra L Martin

PLOS ONE | PUBLIC LIBRARY SCIENCE | Published : 2015

Abstract

Cytochrome P450c17 (P450 17A1, CYP17A1) is a critical enzyme in the synthesis of androgens and is now a target enzyme for the treatment of prostate cancer. Cytochrome P450c17 can exhibit either one or two physiological enzymatic activities differentially regulated by cytochrome b5. How this is achieved remains unknown. Here, comprehensive in silico, in vivo and in vitro analyses were undertaken. Fluorescence Resonance Energy Transfer analysis showed close interactions within living cells between cytochrome P450c17 and cytochrome b5. In silico modeling identified the sites of interaction and confirmed that E48 and E49 residues in cytochrome b5 are essential for activity. Quartz crystal microb..

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Grants

Awarded by National Institutes of Health


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Funding Acknowledgements

Funding: LLM and AMB thank the Australian Research Council, RJR the National Health and Medical Research Council and RJA the National Institutes of Health (R01GM086596) for funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.