AI Article Synopsis

  • Human steroid hormone biosynthesis involves complex chemical changes of cholesterol, largely orchestrated by cytochrome P450 enzymes.
  • The process of forming the male hormone dehydroepiandrosterone starts with pregnenolone being modified by the enzyme CYP17A1, which first adds a hydroxyl group and then breaks a bond, releasing acetic acid.
  • Experiments using kinetic isotope effects indicate that while hydroxylation has a small positive isotope effect, the bond cleavage step shows a large inverse isotope effect, implying a reactive ferric peroxoanion is involved in this reaction.

Article Abstract

Human steroid hormone biosynthesis is the result of a complex series of chemical transformations operating on cholesterol, with key steps mediated by members of the cytochrome P450 superfamily. In the formation of the male hormone dehydroepiandrosterone, pregnenolone is first hydroxylated by P450 CYP17A1 at the 17-carbon, followed a second round of catalysis by the same enzyme that cleaves the C17-C20 bond, releasing acetic acid and the 17-keto product. In order to explore the mechanism of this C-C "lyase" activity, we investigated the kinetic isotope effect on the steady-state turnover of Nanodisc-incorporated CYP17A1. Our experiments revealed the expected small positive (~1.3) isotope effect for the hydroxylase chemistry. However, a surprising result was the large inverse isotope effect (~0.39) observed for the C-C bond cleavage activity. These results strongly suggest that the P450 reactive intermediate involved in this latter step is an iron-bound ferric peroxoanion.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867208PMC
http://dx.doi.org/10.1021/ja4086403DOI Listing

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