Abstract
Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyzes the activation of its substrate 8-oxogeranial into a reactive enol intermediate, but does not catalyze the subsequent cyclization into nepetalactol. This discovery led us to identify a class of nepetalactol-related short-chain dehydrogenase enzymes (NEPS) from catmint (Nepeta mussinii) that capture this reactive intermediate and catalyze the stereoselective cyclisation into distinct nepetalactol stereoisomers. Subsequent oxidation of nepetalactols by NEPS1 provides nepetalactones, metabolites that are well known for both insect-repellent activity and euphoric effect in cats. Structural characterization of the NEPS3 cyclase reveals that it binds to NAD+ yet does not utilize it chemically for a non-oxidoreductive formal [4 + 2] cyclization. These discoveries will complement metabolic reconstructions of iridoid and monoterpene indole alkaloid biosynthesis.
Original language | English |
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Pages (from-to) | 71-79 |
Number of pages | 8 |
Journal | NATURE CHEMICAL BIOLOGY |
Volume | 15 |
Issue number | 1 |
DOIs | |
Publication status | Published - 10 Dec 2018 |
Bibliographical note
© 2018 Springer Nature Publishing AG. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.Keywords
- Alkyl and Aryl Transferases/chemistry
- Binding Sites
- Bridged Bicyclo Compounds, Heterocyclic/metabolism
- Crystallography, X-Ray
- Cyclization
- Iridoids/metabolism
- Monoterpenes/metabolism
- Nepeta/genetics
- Oxidation-Reduction
- Oxidoreductases/metabolism
- Plant Proteins/chemistry
- Serine/genetics