Molecular Recognition in Biological Systems: Phosphate Esters vs Sulfate Esters and the Mechanism of Action of Steroid Sulfatases

摘要

The enzyme-catalyzed desulfation of steroids is a transformation that plays an important role in biological processes as diverse as fertilization, breast cancer and cholesterol transport and metabolism. This communication describes the development of potent inhibitors of steroid sulfatase. A proposed binding mode for these inhibitors based on a transition state analogy (or alternatively a ground state bisubstrate mimic) is then incorporated into a model for the mechanism of action of this enzyme. Steroid sulfation is one of the most common of all forms of steroid conjugation. With the exception of cholesterol, dehy-droepiandrosterone sulfate (1) is the most abundant of all plasma steroids. In addition, estrone sulfate (2) is the most abundant of all the estrogens. In vivo, steroid sulfatases are responsible for the deconjugation of these steroids, an action that is normally required before the steroid can execute its proper biological function. Steroid sulfatase activity is commonly found in a variety of tissue types, but it is particularly prevalent in placenta and in breast tumors. Because breast tumors show high levels of estrone sulfatase activity and a substantial percentage of breast tumors are estrogen dependent, the sulfatase expressed in breast tumors has become a target for chemotherapeutic intervention in breast cancer. However, relatively little is known about the mechanism of action of this group of enzymes. Indeed, sulfatases as a whole remain the most poorly understood of all the major classes of hydrolytic enzymes.