Lord of the rings--the mechanism for oxidosqualene:lanosterol cyclase becomes crystal clear

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 cataly...

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Published inTrends in pharmacological sciences (Regular ed.) Vol. 26; no. 7; pp. 335 - 340
Main Authors Huff, Murray W, Telford, Dawn E
Format Journal Article
LanguageEnglish
Published England 01.07.2005
Subjects
Animals
Anticholesteremic Agents - pharmacology
Cholesterol - biosynthesis
Crystallization
Humans
Intramolecular Transferases - antagonists & inhibitors
Intramolecular Transferases - chemistry
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Summary: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.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-3
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ObjectType-Review-1
ISSN:0165-6147
1873-3735
DOI:10.1016/j.tips.2005.05.004