Biosynthetic Mechanism of Lanosterol: Cyclization.

Chen N, Wang S, Smentek L, Hess BA, Wu R
Angew Chem Int Ed Engl. 2015 54 (30): 8693-6

PMID: 26069216 · DOI:10.1002/anie.201501986

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.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

MeSH Terms (9)

Biosynthetic Pathways Cyclization Humans Intramolecular Transferases Kinetics Lanosterol Models, Molecular Squalene Thermodynamics

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