Studies on bovine adrenal estrogen sulfotransferase. Inhibition and possible involvement of adenine-estrogen stacking.

The inhibition of bovine adrenal estrogen sulfotransferase has been studied utilizing representative androgens and estrogens with structural changes in rings A, B, and D. These investigations have shown oxygen functions in positions 3, 16, or 17 to be required for the binding of estrogens or androgens to the enzyme. 5alpha-Androstanes (all transfused rings) are weak noncompetitive inhibitors and bind more tightly than the 5beta isomers (cis-fused A and B rings). The competitive inhibition observed with the estrogens does not require a free 3-phenolic hydroxyl, however, groups larger than 3-methoxy limit binding. While the product, estrone sulfate, is not inhibitory, phosphate esters on positions 3- or 17beta or a sulfate moiety on the 17beta-hydroxyl group of estrogens slightly inhibit the enzyme. The stacking of adenine (in adenosine 3'-phosphate-5'-phosphosulfate) with the A ring of estrogens is postulated for the enzyme-bound transition state. This structure, which facilitates the hydrogen bonding between the 6-amino group of adenine and the 4-nitro, 4-bromo, or 6-keto substituents on estrogens, readily explains the unusual substrate and inhibitory properties of these compounds. Certain of these estrogen derivatives, which possess little or no hormonal activity, are efficient inhibitors of estrogen sulotransferase.