Conversion of a 3-Desoxysteroid to 3-Desoxyestrogen by Human Placental Aromatase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 87; no. 8; pp. 2999 - 3003
• Main Authors: Cole, Philip A., Bean, Joseph M., Robinson, Cecil H.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-04-1990; National Acad Sciences
• Subjects: 3-desoxyestrogen; Analytical, structural and metabolic biochemistry; Androgens; Aromatase - metabolism; Aromatase inhibitors; Binding, Competitive; Biochemistry; Biological and medical sciences; Enzymes and enzyme inhibitors; Estrogens; Estrogens - biosynthesis; Ethers; Female; Fundamental and applied biological sciences. Psychology; Humans; Hydrogen; Indicators and Reagents; Kinetics; Magnetic Resonance Spectroscopy; Microsomes; Oxidoreductases; Peroxides; placenta; Placenta - enzymology; Pregnancy; Steroids; Steroids - chemical synthesis; Substrate Specificity; Testosterone; Human; Androgen; Molecular structure; Cytochrome P450; Estrogen; Competitive inhibition; Substrate analog; Placenta; Enolization; Oestrogen synthase; Peroxides; Sex steroid hormone; Mechanism of action
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.87.8.2999

Human placental aromatase is a cytochrome P-450 enzyme system which converts androgens to estrogens by three successive oxidative reactions. The first two steps have been shown to be hydroxylations at the androgen 19-carbon, but the third step remains unknown. A leading theory for the third step involves ferric peroxide attack on the 19-oxo group to produce a 19,19-hydroxyferric peroxide intermediate and subsequent collapse to estrogen. We had previously developed a nonenzymatic peroxide model reaction which was based on the above-mentioned theory, and we demonstrated the importance of 3-ketone enolization in facilitating aromatization. This study discusses the synthesis and nonenzymatic and enzymatic study of a 3-desoxy-2,4-diene-19-oxo androgen analogue. This compound was found to be a potent nonenzymatic model substrate and competitive inhibitor of aromatase (Ki= 73 nM). Furthermore, in an unprecedented event, this compound served as a substrate for aromatase, with conversion to the corresponding 3-desoxyestrogen.