title: Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase.
abstract: 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.
authors.affiliation: F. Hoffmann-La Roche AG, Pharma Research Discovery Chemistry, 4070 Basel, Switzerland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Thoma
authors.forename: Tanja
authors.initials: T
authors.lastname: Schulz-Gasch
authors.forename: Brigitte
authors.initials: B
authors.lastname: D'Arcy
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Johannes
authors.initials: J
authors.lastname: Aebi
authors.forename: Henrietta
authors.initials: H
authors.lastname: Dehmlow
authors.forename: Michael
authors.initials: M
authors.lastname: Hennig
authors.forename: Martine
authors.initials: M
authors.lastname: Stihle
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D018360:Crystallography, X-Ray; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D007810:Lanosterol / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D013185:Squalene / Q000031:analogs & derivatives* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C002821:2,3-oxidosqualene; D000924:Anticholesteremic Agents; D001577:Benzophenones; C105726:Ro 48-8071; D007810:Lanosterol; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase