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

Ralf Thoma, Tanja Schulz-Gasch, Brigitte D'Arcy, Jörg Benz, Johannes Aebi, Henrietta Dehmlow, Michael Hennig, Martine Stihle and Armin Ruf ()
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Ralf Thoma: Pharma Research Discovery Chemistry
Tanja Schulz-Gasch: Pharma Research Discovery Chemistry
Brigitte D'Arcy: Pharma Research Discovery Chemistry
Jörg Benz: Pharma Research Discovery Chemistry
Johannes Aebi: Pharma Research Discovery Chemistry
Henrietta Dehmlow: Pharma Research Discovery Chemistry
Michael Hennig: Pharma Research Discovery Chemistry
Martine Stihle: Pharma Research Discovery Chemistry
Armin Ruf: Pharma Research Discovery Chemistry

Nature, 2004, vol. 432, issue 7013, 118-122

Abstract: 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 reaction1,2. 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 statins3. 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.

Date: 2004
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DOI: 10.1038/nature02993

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