Estrone Sulfatase: Probing Structural Requirements for Substrate and Inhibitor Recognition

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Abstract
The enzyme-catalyzed desulfation of steroids is a transformation that plays an important role in steroid biosynthesis. Conversion of steroid sulfates to unconjugated steroids may provide a source of steroids for processes such as steroid transport and the growth and proliferation of breast cancer. Steroid sulfatase catalyzes the hydrolysis of 3β-hydroxysteroid sulfates. To identify structural features important in enzyme−inhibitor interaction, a variety of steroidal and non-steroidal phosphate esters were synthesized and tested as inhibitors of steroid sulfatase activity. We report that the basic structure for enzyme−inhibitor binding does not include the steroid nucleus. Furthermore, the hydrophobicity of the non-steroidal phosphates was determined to be an important factor for optimal inhibition. The monoanionic form of the phosphorylated compounds was found to be the inhibitory species. The best non-steroidal inhibitor of steroid sulfatase activity was n-lauroyl tryamine phosphate with a Ki of 3.6 μM and 520 nM at pH 7.5 and 7.0. The poorest non-steroidal based inhibitor of sulfatase activity was tetrahydronaphthyl phosphate with a Ki of 870 and 360 μM at pH 7.5 and 7.0.