Total Biosynthesis of Melleolides from Basidiomycota Fungi: Mechanistic Analysis of the Multifunctional GMC Oxidase Mld7

Author:

Fukaya Mitsunori1,Nagamine Shota1,Ozaki Taro1,Liu Yaping1,Ozeki Miina1,Matsuyama Taro2,Miyamoto Kazunori2,Kawagishi Hirokazu34,Uchiyama Masanobu2,Oikawa Hideaki15,Minami Atsushi1ORCID

Affiliation:

1. Department of Chemistry Faculty of Science Hokkaido University Sapporo 060-0810 Japan

2. Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo 113-0033 Japan

3. Faculty of Agriculture Shizuoka University Shizuoka 422-8526 Japan

4. Research Institute for Mushroom Science Shizuoka 422-8529 Japan

5. Innovation Center of Marine Biotechnology and Pharmaceuticals School of Biotechnology and Health Sciences Wuyi University Jiangmen 529020 China

Abstract

AbstractMushroom terpenoids are biologically and chemically diverse fungal metabolites. Among them, melleolides are representative sesquiterpenoids with a characteristic protoilludane skeleton. In this study, we applied a recently established hot spot knock‐in method to elucidate the biosynthetic pathway leading to 1α‐hydroxymelleolide. The biosynthesis of the sesquiterpene core involves the cytochrome P450 catalyzing stepwise hydroxylation of the Δ6‐protoilludene framework and a stereochemical inversion process at the C5 position catalyzed by short‐chain dehydrogenase/reductase family proteins. The highlight of the biosynthesis is that the flavoprotein Mld7 catalyzes an oxidation‐triggered double‐bond shift accompanying dehydration and acyl‐group‐assisted substitution with two different nucleophiles at the C6 position to afford the Δ7‐protoilludene derivatives, such as melleolide and armillarivin. The complex reaction mechanism was proposed by DFT calculations. Of particular importance is that product distribution is regulated by interaction with the cell membrane.

Funder

Japan Society for the Promotion of Science

Uehara Memorial Foundation

Publisher

Wiley

Subject

General Medicine

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