title: Lord of the rings--the mechanism for oxidosqualene:lanosterol cyclase becomes crystal clear.
abstract: The enzyme oxidosqualene:lanosterol cyclase (OSC) represents a novel target for the treatment of hypercholesterolemia. OSC catalyzes the cyclization of the linear 2,3-monoepoxysqualene to lanosterol, the initial four-ringed sterol intermediate in the cholesterol biosynthetic pathway. OSC also catalyzes the formation of 24(S),25-epoxycholesterol, a ligand activator of the liver X receptor. Inhibition of OSC reduces cholesterol biosynthesis and selectively enhances 24(S),25-epoxycholesterol synthesis. Through this dual mechanism, OSC inhibition decreases plasma levels of low-density lipoprotein (LDL)-cholesterol and prevents cholesterol deposition within macrophages. The recent crystallization of OSC identifies the mechanism of action for this complex enzyme, setting the stage for the design of OSC inhibitors with improved pharmacological properties for cholesterol lowering and treatment of atherosclerosis.
authors.affiliation: Robarts Research Institute, Vascular Biology Group, Departments of Medicine and Biochemistry, The University of Western Ontario, London, Ontario N6A 5K8, Canada. mhuff@uwo.ca
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D003460:Crystallization; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000924:Anticholesteremic Agents; D002784:Cholesterol; D019751:Intramolecular Transferases; C021924:lanosterol synthase