Chemical Control in the Battle against Fidelity in Promiscuous Natural Product Biosynthesis: The Case of Trichodiene Synthase

Mudit Dixit, Michal Weitman, Jiali Gao, Dan T. Major

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Terpene cyclases catalyze the highly stereospecific molding of polyisoprenes into terpenes, which are precursors to most known natural compounds. The isoprenoids are formed via intricate chemical cascades employing rich, yet highly erratic, carbocation chemistry. It is currently not well understood how these biocatalysts achieve chemical control. Here, we illustrate the catalytic control exerted by trichodiene synthase, and in particular, we discover two features that could be general catalytic tools adopted by other terpenoid cyclases. First, to avoid formation of byproducts, the enzyme raises the energy of bisabolyl carbocation, which is a general mechanistic branching point in many sesquiterpene cyclases, resulting in an essentially concerted cyclization cascade. Second, we identify a sulfur-carbocation dative bonding interaction that anchors the bisabolyl cation in a reactive conformation, avoiding tumbling and premature deprotonation. Specifically, Met73 acts as a chameleon, shifting from an initial sulfur-π interaction in the Michaelis complex to a sulfur-carbocation complex during catalysis.

Original languageEnglish (US)
Pages (from-to)812-818
Number of pages7
JournalACS Catalysis
Volume7
Issue number1
DOIs
StatePublished - Jan 6 2017

Bibliographical note

Funding Information:
This work has been supported by the Israel Science Foundation (Grant No. 2146/15) and the National Institutes of Health (Grant GM46736).

Keywords

  • QM/MM simulations
  • enzyme catalysis
  • sulfur-cation interaction
  • sulfur-π interaction
  • terpene cyclases

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