Mechanistically informed predictions of binding modes for carbocation intermediates of a sesquiterpene synthase reaction

Chemical Science
Terrence E O'BrienJustin B Siegel

Abstract

Sesquiterpenoids comprise a class of terpenoid natural products with thousands of compounds that are highly diverse in structure, generally containing a polycyclic carbon backbone that is constructed by a sesquiterpene synthase. Decades of experimental and computational studies have demonstrated that these enzymes generate a carbocation in the active site, which undergoes a series of structural rearrangements until a product is formed via deprotonation or nucleophile attack. However, for the vast majority of these enzymes the productive binding orientation of the intermediate carbocations has remained unclear. In this work, a method that combines quantum mechanics and computational docking is used to generate an all-atom model of every putative intermediate formed in the context of the enzyme active site for tobacco epi-aristolochene synthase (TEAS). This method identifies a single pathway that links the first intermediate to the last, enabling us to propose the first high-resolution model for the reaction intermediates in the active site of TEAS, and providing testable predictions.

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Citations

Mar 9, 2019·Frontiers in Plant Science·Samuel Jacobus SmitPhilip Richard Young
Aug 31, 2019·Beilstein Journal of Organic Chemistry·Hajime SatoMasanobu Uchiyama
Mar 2, 2017·Organic & Biomolecular Chemistry·Patrick RabeJeroen S Dickschat
Jul 18, 2020·Current Opinion in Biotechnology·Keren RazDan Thomas Major
Mar 24, 2020·European Journal of Medicinal Chemistry·Bogdan BarnychBruce D Hammock
Mar 27, 2021·Angewandte Chemie·Andreas SchneiderBernhard Hauer
Feb 23, 2019·Journal of Chemical Information and Modeling·Kara E RanaghanAdrian J Mulholland
Aug 7, 2019·Journal of Chemical Theory and Computation·Susanta DasDan T Major
Oct 21, 2021·Chembiochem : a European Journal of Chemical Biology·Nicole G H Leferink, Nigel S Scrutton

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Methods Mentioned

BETA
X-ray

Software Mentioned

Gaussian09
Spartan
Rosetta
MMFF
TMalign
TEAS

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