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- Title
Biosynthetic Mechanism of Lanosterol: Cyclization.
- Authors
Chen, Nanhao; Wang, Shenglong; Smentek, Lidia; Hess, B. Andes; Wu, Ruibo
- 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.
- Subjects
BIOSYNTHESIS; LANOSTEROL; RING formation (Chemistry); ANTI-Markovnikov reaction; QUANTUM mechanics
- Publication
Angewandte Chemie International Edition, 2015, Vol 54, Issue 30, p8693
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201501986