Estrone sulfatase: probing structural requirements for substrate and inhibitor recognition.

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 3beta-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 microM 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 microM at pH 7.5 and 7.0.

• Authors: C Anderson, J Freeman, L H Lucas, M Farley, H Dalhoumi, T S Widlanski
• Journal: Biochemistry (Biochemistry) Vol. 36 Issue 9 Pg. 2586-94 (Mar 04 1997) ISSN: 0006-2960 [Print] United States
• PMID: 9054565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chromogenic Compounds
• Enzyme Inhibitors
• Organophosphates
• Sulfates
• Water
• Estrone
• Dehydroepiandrosterone
• Sulfatases
• estrone sulfatase
• Tyramine

Topics

• Chromogenic Compounds
• Dehydroepiandrosterone (analogs & derivatives, metabolism)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Estrone (analogs & derivatives, metabolism)
• Humans
• Hydrogen-Ion Concentration
• Kinetics
• Magnetic Resonance Spectroscopy
• Organophosphates (metabolism)
• Placenta
• Structure-Activity Relationship
• Substrate Specificity
• Sulfatases (antagonists & inhibitors, chemistry, metabolism)
• Sulfates (metabolism)
• Tyramine (analogs & derivatives, metabolism)
• Water