Mechanism-Based Inhibitors and Other Active-Site Targeted Inhibitors of Oxidosqualene Cyclase and Squalene Cyclase

Abstract

Enzymatic cyclizations of squalene and oxidosqualene lead to sterols and other triterpenoids in bacteria, fungi, plants, and animals. The cyclases for these reactions catalyze formation and stabilization of polycyclic carbocations and direct the enzyme-specific, templated formation of new carbon-carbon bonds in regio- and stereochemically defined contexts. The development of mechanism-based irreversible inhibitors, photoactivatable inhibitors, and numerous substrate analogs have helped to unravel the stepwise events occurring in the catalytic sites of these enzymes by covalent modification of specific amino acid residues.

Key Words:

• Suicide substrate
• Cholesterol biogenesis
• Polyolefin cyclization
• Cation mimics
• Pholoaffinity label
• Covalent modification