Faculty Collaboration Database

Unveiling the crucial intermediates in androgen production. Proc Natl Acad Sci U S A 2015 Dec 29;112(52):15856-61

Date

12/17/2015

Pubmed ID

26668369

Pubmed Central ID

PMC4703009

DOI

10.1073/pnas.1519376113

Scopus ID

2-s2.0-84952674074 (requires institutional sign-in at Scopus site)   62 Citations

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.

Author List

Mak PJ, Gregory MC, Denisov IG, Sligar SG, Kincaid JR

Author

James Kincaid PhD Department Chair and Professor, Biophysical Chemistry in the Chemistry department at Marquette University

MESH terms used to index this publication - Major topics in bold

17-alpha-Hydroxypregnenolone
Androgens
Biocatalysis
Biosynthetic Pathways
Dehydroepiandrosterone
Humans
Hydrogen Bonding
Hydroxylation
Models, Chemical
Models, Molecular
Molecular Structure
Pregnenolone
Protein Conformation
Spectrophotometry
Steroid 17-alpha-Hydroxylase
Substrate Specificity
Temperature