title: Biosynthetic Mechanism of Lanosterol: Cyclization.
abstract: The remarkable cyclization mechanism of the formation of the 6-6-6-5 tetracyclic lanosterol (a key triterpenoid intermediate in the biosynthesis of cholesterol) from the acyclic 2,3-oxidosqualene catalyzed by oxidosqualene cyclase (OSC) has stimulated the interest of chemists and biologists for over a half century. Herein, the elaborate, state-of-the-art two-dimensional (2D) QM/MM MD simulations have clearly shown that the cyclization of the A-C rings involves a nearly concerted, but highly asynchronous cyclization, to yield a stable intermediate with "6-6-5" rings followed by the ring expansion of the C-ring concomitant with the formation of the D-ring to yield the "6-6-6-5" protosterol cation. The calculated reaction barrier of the rate-limiting step (≈22 kcal mol(-1)) is comparable to the experimental kinetic results. Furthermore all previous experimental mutagenic evidence is highly consistent with the identified reaction mechanism.
authors.affiliation: School of Pharmaceutical Science, Sun Yet-sen University, Guangzhou, 510006 (China).
authors.forename: Nanhao
authors.initials: N
authors.lastname: Chen
authors.affiliation: Information Technology Services, New York University, New York, NY10003 (USA).
authors.forename: Shenglong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN37235 (USA).
authors.forename: Lidia
authors.initials: L
authors.lastname: Smentek
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN37235 (USA). b.andes.hess@vanderbilt.edu.
authors.forename: B Andes
authors.initials: BA
authors.lastname: Hess
authors.affiliation: School of Pharmaceutical Science, Sun Yet-sen University, Guangzhou, 510006 (China). wurb3@mail.sysu.edu.cn.
authors.forename: Ruibo
authors.initials: R
authors.lastname: Wu
mesh_terms: D053898:Biosynthetic Pathways; D003500:Cyclization; D006801:Humans; D019751:Intramolecular Transferases / Q000378:metabolism*; D007700:Kinetics; D007810:Lanosterol / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D013185:Squalene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: C002821:2,3-oxidosqualene; D007810:Lanosterol; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase
keywords: QM/MM; biosynthesis; cyclization; lanosterol; oxidosqualane cyclase