Theoretical studies on the mechanism of conversion of androgens to estrogens by aromatase

• Published in: Biochemistry (Easton) Vol. 30; no. 25; pp. 6155 - 6162
• Main Authors: Korzekwa, Kenneth R, Trager, William F, Smith, Soozy J, Osawa, Yoichi, Gillette, James R
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 25.06.1991
• Subjects: Analytical, structural and metabolic biochemistry; androgens; Androgens - metabolism; Androstenols - metabolism; aromatase; Aromatase - metabolism; Biological and medical sciences; conversion; Enzyme Activation; Enzyme Stability; Enzymes and enzyme inhibitors; estrogens; Estrogens - metabolism; Free Radicals; Fundamental and applied biological sciences. Psychology; Hydrolysis; Hydroxides - metabolism; Hydroxyl Radical; Ketones - metabolism; mechanisms; Oxidoreductases; Oxygen - metabolism; Sulfur - metabolism; Thermodynamics; Theoretical model; Androgen; Enzyme; Estrogen; Reaction mechanism; Oestrogen synthase; Sex steroid hormone
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi00239a011

Semiempirical molecular orbital calculations (AM1) were used to model several possible reaction mechanisms for the third oxidation of the aromatase-catalyzed conversion of androgens to estrogens. The reaction mechanisms considered are based on the assumption that the third oxidation is initiated by 1 beta-hydrogen atom abstraction. Homolytic cleavage of the C10-C19 bond was modeled for both the 3-keto and 2-en-3-ol forms of the androgen 1-radicals. The addition of a protein nucleophile to the 19-oxo intermediate was also considered, and -OCH3, -SCH3, and -NHCH3 were used to represent the Ser, Cys, and Lys adducts. The transition states were estimated and optimized from the reaction coordinates obtained by constraining and increasing the C10-C19 bond lengths. The enthalpies of activation range from 14 to 21 kcal and are approximately 2 kcal lower for cleavage of the enol form. Given the tendency for AM1 to overestimate activation energies, all reactions may be energetically accessible. Other reactions modeled include a homolytic cleavage reaction from a thioether radical cation and the direct additions of oxygen radical compounds to the carbonyl of the 1-radical-2-en-3-ol-19-oxo androgen. A mechanism is proposed in which the 19-oxo intermediate is subject to initial nucleophilic attack by the protein. Since rotation of the 19-carbonyl can bring the oxygen within 2.1 A of the 2 beta-hydrogen, the formation of a tetrahedral intermediate can occur with concomitant removal of the 2 beta-proton. Enolization activates the C1-position for hydrogen atom abstraction, since the resulting radical is resonance stabilized.