Steroid Aromatase Dark Horse Wins

Enzyme specialists believe they have finally nailed down the controversial mechanism of a key mammalian hormone conversion process called the steroid aromatase reaction (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja508185d). The conversion of androgens to estrogens maintains the proper balance of sex hormones in the body. And cytochrome P450 19A1, the iron-dependent aromatase enzyme that catalyzes the reaction, is a drug target for estrogen-dependent breast, uterine, and ovarian cancers. Researchers have therefore been trying to determine how the reaction works at a detailed molecular level. But the active iron species in the form of the enzyme involved in the third and final step of the reaction has been uncertain—no fewer than five mechanisms have been proposed. Some studies support an FeO³⁺ species called Compound I, but a more favored mechanism involves ferric peroxide (FeO^2–) instead. Francis K. Yoshimoto and F. Peter Guengerich of Vanderbilt University School of Medicine have now used isotopic labeling to provide definitive evidence that Compound I is the active iron species in the third step, beating out the more favored proposal.