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Taming the reactivity of monoterpene synthases to guide regioselective product hydroxylation

Research output: Contribution to journalArticle

Original languageEnglish
Number of pages7
JournalChemBioChem
DOIs
DateAccepted/In press - 4 Nov 2019
DatePublished (current) - 3 Dec 2019

Abstract

Monoterpenoids are industrially important natural products
with applications in the flavours, fragrances, fuels and pharmaceutical
industries. Most monoterpenoids are produced by plants, but recently
two bacterial monoterpene synthases have been identified, including
a cineole synthase (bCinS). Unlike plant cineole synthases, bCinS is
capable of producing nearly pure cineole from geranyl diphosphate in
a complex cyclisation cascade that is tightly controlled. Here we have
used a multidisciplinary approach to show that Asn305 controls water
attack on the α-terpinyl cation and subsequent cyclisation and deprotonation of the α-terpineol intermediate, key steps in the cyclisation
cascade which direct product formation towards cineole. Mutation of
Asn305 results in variants that no longer produce α-terpineol or
cineole. MD simulations revealed that water coordination is disrupted
in all variants tested. QM calculations indicate that Asn305 is most
likely a (transient) proton acceptor for the final deprotonation step. Our
synergistic approach gives unique insights into how a single residue,
Asn305, tames the promiscuous chemistry of monoterpene synthase
cyclisation cascades. It does this by tightly controlling the final steps
in cineole formation catalysed by bCinS to form a single hydroxylated
monoterpene product.

    Research areas

  • Enzyme catalysis, Protein Engineering, Molecular dynamics, Synthetic Biology, Terpenoids

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Wiley at https://onlinelibrary.wiley.com/doi/full/10.1002/cbic.201900672 . Please refer to any applicable terms of use of the publisher.

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