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

T. E. O'Brien, S. J. Bertolani, D. J. Tantillo, Justin Siegel

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4009-4015
Number of pages7
JournalChemical Science
Volume7
Issue number7
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Chemistry(all)

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