Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase

• Published in: Nature 2004-11, Vol.432 (7013), p.118-122
• Main Authors: Ruf, Armin, Thoma, Ralf, Schulz-Gasch, Tanja, D'Arcy, Brigitte, Benz, Jörg, Aebi, Johannes, Dehmlow, Henrietta, Hennig, Michael, Stihle, Martine
• Format: Article
• Language: English
• Subjects: Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacology; Benzophenones - chemistry; Benzophenones - pharmacology; Biological and medical sciences; Biosynthesis; Catalysis; Chemistry; Cholesterol; Crystalline structure; Crystallography, X-Ray; Cyclization; Drug Design; Enzymes; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Humans; Intramolecular Transferases - antagonists & inhibitors; Intramolecular Transferases - chemistry; Intramolecular Transferases - metabolism; Lanosterol - chemistry; Lanosterol - metabolism; letter; Models, Molecular; Molecular biophysics; multidisciplinary; Proteins; Science; Science (multidisciplinary); Squalene - analogs & derivatives; Squalene - metabolism; Statins; Steroids; Structure in molecular biology; Structure-Activity Relationship; Suicide
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02993

In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.