Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase.
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.
Thoma
Ralf
R
F. Hoffmann-La Roche AG, Pharma Research Discovery Chemistry, 4070 Basel, Switzerland.
Schulz-Gasch
Tanja
T
D'Arcy
Brigitte
B
Benz
Jörg
J
Aebi
Johannes
J
Dehmlow
Henrietta
H
Hennig
Michael
M
Stihle
Martine
M
Ruf
Armin
A
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
C002821:2,3-oxidosqualene; D000924:Anticholesteremic Agents; D001577:Benzophenones; C105726:Ro 48-8071; D007810:Lanosterol; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase