Structural and Catalytic Insight into the Unique Pentacyclic Triterpene Synthase TwOSC.
Cryo-EM Structure
Enzyme Catalysis
Oxidosqualene Cyclase
Protein Engineering
QM/MM
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
27 Nov 2023
27 Nov 2023
Historique:
received:
14
09
2023
medline:
27
11
2023
pubmed:
16
10
2023
entrez:
16
10
2023
Statut:
ppublish
Résumé
The oxidosqualene cyclase (OSC) catalyzed cyclization of the linear substrate (3S)-2,3-oxidosqualene to form diverse pentacyclic triterpenoid (PT) skeletons is one of the most complex reactions in nature. Friedelin has a unique PT skeleton involving a fascinating nine-step cation shuttle run (CSR) cascade rearrangement reaction, in which the carbocation formed at C2 moves to the other side of the skeleton, runs back to C3 to yield a friedelin cation, which is finally deprotonated. However, as crystal structure data of plant OSCs are lacking, it remains unknown why the CSR cascade reactions occur in friedelin biosynthesis, as does the exact catalytic mechanism of the CSR. In this study, we determined the first cryogenic electron microscopy structure of a plant OSC, friedelin synthase, from Tripterygium wilfordii Hook. f (TwOSC). We also performed quantum mechanics/molecular mechanics simulations to reveal the energy profile for the CSR cascade reaction and identify key residues crucial for PT skeleton formation. Furthermore, we semirationally designed two TwOSC mutants, which significantly improved the yields of friedelin and β-amyrin, respectively.
Identifiants
pubmed: 37840440
doi: 10.1002/anie.202313429
doi:
Substances chimiques
Triterpenes
0
friedelin
AK21264UAD
Intramolecular Transferases
EC 5.4.-
Cations
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202313429Subventions
Organisme : the National Natural Science Foundation of China
ID : 82003894
Organisme : the National Key R&D Program of China
ID : 2020YFA0908000
Organisme : Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan
ID : 2060302
Organisme : Special Project for Research and Development in Key areas of Guangdong Province
ID : 2022B1111080005
Organisme : Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine
ID : ZYYCXTD-D-202005
Informations de copyright
© 2023 Wiley-VCH GmbH.
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