Chemoenzymatic synthesis of (4 R ,7 R )‐zingiberene enables construction of nor‐sesquiterpene semiochemical analogs

Johnson, Luke A. ORCID: https://orcid.org/0000-0002-6697-6589, Benton, Jennifer C. R., Jones, Chris, Kuzba, Oktawia, Miller, David J., Pickett, John A. ORCID: https://orcid.org/0000-0002-8386-3770 and Allemann, Rudolf K. ORCID: https://orcid.org/0000-0002-1323-8830 2026. Chemoenzymatic synthesis of (4 R ,7 R )‐zingiberene enables construction of nor‐sesquiterpene semiochemical analogs. ChemBioChem 27 (19) , e70534. 10.1002/cbic.70534

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Abstract

The wild tomato sesquiterpene (4R,7R)-zingiberene (6a) acts as a potent repellent of the economically important agricultural pest, the silverleaf whitefly (Bemisia tabaci). While its biosynthesis is catalyzed by 7-epi-zingiberene synthase from the noncanonical terpene precursor (2Z,6Z)-farnesyl pyrophosphate (5a), the precise enzymatic mechanism has remained undetermined. Using deuterated substrates generated chemoenzymatically, the 1,6-cyclization mechanism was established to proceed via a 1,3-hydride shift from the C1 position of the initial bisabolyl carbocationic intermediate. Product diversity was expanded by identifying two single residue switches within the G1/2 helix that govern enzyme fidelity, thereby redirecting product distributions to alternative C6-cyclized zingiberenols as well as γ- and β-curcumene. Applying this chemoenzymatic synthesis with alternative allyl alcohols plus isoprenol enabled the production and structural diversification of two novel nor-sesquiterpene analogs (C14/C16), 13-nor-(4R,7R)-zingiberene (23) and 12-ethyl-13-nor-(4R,7R)-zingiberene (24). Notably, these syntheses were only possible because the tomato (2Z,6Z)-farnesyl pyrophosphate synthase overcomes conventional prenyltransferase substrate selectivity to catalyze chain extension via atypical secondary allyl carbocation intermediates. The catalytic promiscuity provides opportunities to engineer terpene products with diverse methyl-branching patterns, providing the platform to investigate the molecular basis of terpene semiochemical activity needed for the development of broad-spectrum repellents to sustainably manage insect pests in agriculture.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Chemistry Schools > Physical, Chemical & Environmental Sciences
Publisher:	Wiley
ISSN:	1439-4227
Date of First Compliant Deposit:	12 October 2026
Date of Acceptance:	27 August 2026
Last Modified:	12 Oct 2026 14:45
URI:	https://orca.cardiff.ac.uk/id/eprint/190168

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