title: Theoretical studies on the mechanism of conversion of androgens to estrogens by aromatase.
abstract: 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: K R
authors.initials: KR
authors.lastname: Korzekwa
authors.forename: W F
authors.initials: WF
authors.lastname: Trager
authors.forename: S J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Y
authors.initials: Y
authors.lastname: Osawa
authors.forename: J R
authors.initials: JR
authors.lastname: Gillette
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000737:Androstenols / Q000378:metabolism; D001141:Aromatase / Q000378:metabolism*; D004789:Enzyme Activation; D004795:Enzyme Stability; D004967:Estrogens / Q000378:metabolism*; D005609:Free Radicals; D006868:Hydrolysis; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D007659:Ketones / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000728:Androgens; D000737:Androstenols; D004967:Estrogens; D005609:Free Radicals; D006878:Hydroxides; D007659:Ketones; D017665:Hydroxyl Radical; D013455:Sulfur; D001141:Aromatase; D010100:Oxygen