Rational Design and Synthesis of Enzyme Inhibitors : Significance in Probing the Function of Enzymes

Abstract

Selective inhibitors of enzymes are useful tools to unravel the chemical and biological functions of enzymes. In particular, stable compounds that resemble the transition state (transition-state analogs) are extremely useful in understanding the catalysis of enzymes from the structural and mechanistic points of view, because the basic principle underlying enzyme catalysis is to stabilize the transition state selectively. According to this principle, we have designed and synthesized a series of phosphinate- and sulfoximine-based transition-state analog inhibitors of ATP-dependent ligases such as γ-glutamylcysteine synthetase, glutathione synthetase and asparagine synthetase A. We also synthesized a monofluorophosphonate derivative of glutamic acid for mechanism-based affinity labeling of γ-glutamyl transpeptidase. These inhibitors have been used successfully for the X-ray crystallography or mass analysis of the enzymes to identify the key catalytic residues responsible for catalysis, and for understanding the recognition of the substrate in the transition state in energetic terms.