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Uncoupled activation and cyclization in catmint reductive terpenoid biosynthesis

DOI: 10.1038/s41589-018-0185-2 DOI Help

Authors: Benjamin R. Lichman (The John Innes Centre) , Mohamed O. Kamileen (The John Innes Centre) , Gabriel R. Titchiner (The John Innes Centre) , Gerhard Saalbach (The John Innes Centre) , Clare E. M. Stevenson (The John Innes Centre) , David M. Lawson (The John Innes Centre) , Sarah E. O'Connor (The John Innes Centre)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 15 , PAGES 71 - 79

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 13467

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 effects 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.

Journal Keywords: Biosynthesis; Enzyme mechanisms; Enzymes; X-ray crystallography

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Added On: 14/01/2019 14:47

Discipline Tags:

Catalysis Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)