Issue 7, 2016

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

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
10 Feb 2016
Accepted
18 Mar 2016
First published
21 Mar 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2016,7, 4009-4015

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

T. E. O'Brien, S. J. Bertolani, D. J. Tantillo and J. B. Siegel, Chem. Sci., 2016, 7, 4009 DOI: 10.1039/C6SC00635C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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