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Enzyme-Catalyzed Inverse-Electron Demand Diels-Alder Reaction in the Biosynthesis of Antifungal Ilicicolin H.

ABSTRACT: The pericyclases are a growing superfamily of enzymes that catalyze pericyclic reactions. We report a pericyclase IccD catalyzing an inverse-electron demand Diels-Alder (IEDDA) reaction with a rate acceleration of 3 × 105-fold in the biosynthesis of fungal natural product ilicicolin H. We demonstrate IccD is highly periselective toward the IEDDA cycloaddition over a competing normal electron demand Diels-Alder (NEDDA) reaction from an ambimodal transition state. A predicted flavoenzyme IccE was identified to epimerize the IEDDA product 8- epi-ilicicolin H to ilicicolin H, a step that is critical for the observed antifungal activity of ilicicolin H. Our results reveal the ilicicolin H biosynthetic pathway and add to the collection of pericyclic reactions that are catalyzed by pericyclases.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6585442 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Enzyme-Catalyzed Inverse-Electron Demand Diels-Alder Reaction in the Biosynthesis of Antifungal Ilicicolin H.

Zhang Zhuan Z Jamieson Cooper S CS Zhao Yi-Lei YL Li Dehai D Ohashi Masao M Houk K N KN Tang Yi Y

Journal of the American Chemical Society 20190326 14

The pericyclases are a growing superfamily of enzymes that catalyze pericyclic reactions. We report a pericyclase IccD catalyzing an inverse-electron demand Diels-Alder (IEDDA) reaction with a rate acceleration of 3 × 10<sup>5</sup>-fold in the biosynthesis of fungal natural product ilicicolin H. We demonstrate IccD is highly periselective toward the IEDDA cycloaddition over a competing normal electron demand Diels-Alder (NEDDA) reaction from an ambimodal transition state. A predicted flavoenzym ...[more]

PMID: 30905148

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