Discovery and characterization of a terpene biosynthetic pathway featuring a norbornene-forming Diels-Alderase

Zuodong Sun, Cooper S. Jamieson, Masao Ohashi, K. N. Houk () and Yi Tang ()
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Zuodong Sun: University of California, Los Angeles
Cooper S. Jamieson: University of California, Los Angeles
Masao Ohashi: University of California, Los Angeles
K. N. Houk: University of California, Los Angeles
Yi Tang: University of California, Los Angeles

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Pericyclases, enzymes that catalyze pericyclic reactions, form an expanding family of enzymes that have biocatalytic utility. Despite the increasing number of pericyclases discovered, the Diels-Alder cyclization between a cyclopentadiene and an olefinic dienophile to form norbornene, which is among the best-studied cycloadditions in synthetic chemistry, has surprisingly no enzymatic counterpart to date. Here we report the discovery of a pathway featuring a norbornene synthase SdnG for the biosynthesis of sordaricin-the terpene precursor of antifungal natural product sordarin. Full reconstitution of sordaricin biosynthesis reveals a concise oxidative strategy used by Nature to transform an entirely hydrocarbon precursor into the highly functionalized substrate of SdnG for intramolecular Diels-Alder cycloaddition. SdnG generates the norbornene core of sordaricin and accelerates this reaction to suppress host-mediated redox modifications of the activated dienophile. Findings from this work expand the scopes of pericyclase-catalyzed reactions and P450-mediated terpene maturation.

Date: 2022
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DOI: 10.1038/s41467-022-30288-6

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