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Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):15856-61. doi: 10.1073/pnas.1519376113. Epub 2015 Dec 14.

Unveiling the crucial intermediates in androgen production.

Author information

1
Department of Chemistry, Marquette University, Milwaukee, WI 53233;
2
Department of Biochemistry, University of Illinois, Urbana, IL 61801;
3
Department of Biochemistry, University of Illinois, Urbana, IL 61801; Department of Chemistry, University of Illinois, Urbana, IL 61801; College of Medicine, University of Illinois, Urbana, IL 61801 s-sligar@illinois.edu james.kincaid@marquette.edu.
4
Department of Chemistry, Marquette University, Milwaukee, WI 53233; s-sligar@illinois.edu james.kincaid@marquette.edu.

Abstract

Ablation of androgen production through surgery is one strategy against prostate cancer, with the current focus placed on pharmaceutical intervention to restrict androgen synthesis selectively, an endeavor that could benefit from the enhanced understanding of enzymatic mechanisms that derives from characterization of key reaction intermediates. The multifunctional cytochrome P450 17A1 (CYP17A1) first catalyzes the typical hydroxylation of its primary substrate, pregnenolone (PREG) and then also orchestrates a remarkable C17-C20 bond cleavage (lyase) reaction, converting the 17-hydroxypregnenolone initial product to dehydroepiandrosterone, a process representing the first committed step in the biosynthesis of androgens. Now, we report the capture and structural characterization of intermediates produced during this lyase step: an initial peroxo-anion intermediate, poised for nucleophilic attack on the C20 position by a substrate-associated H-bond, and the crucial ferric peroxo-hemiacetal intermediate that precedes carbon-carbon (C-C) bond cleavage. These studies provide a rare glimpse at the actual structural determinants of a chemical transformation that carries profound physiological consequences.

KEYWORDS:

cytochrome P450; nanodiscs; peroxo-hemiacetal; resonance Raman spectroscopy; steroids

PMID:
26668369
PMCID:
PMC4703009
DOI:
10.1073/pnas.1519376113
[Indexed for MEDLINE]
Free PMC Article

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