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Uncovering biosynthetic relationships between antifungal nonadrides and octadrides

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Abstract

Maleidrides are a class of bioactive secondary metabolites unique to filamentous fungi, which contain one or more maleic anhydrides fused to a 7-, 8- or 9- membered carbocycle (named heptadrides, octadrides and nonadrides respectively). Herein structural and biosynthetic studies on the antifungal octadride, zopfiellin, and nonadrides scytalidin, deoxyscytalidin and castaneiolide are described. A combination of genome sequencing, bioinformatic analyses, gene disruptions, biotransformations, isotopic feeding studies, NMR and X-ray crystallography revealed that they share a common biosynthetic pathway, diverging only after the nonadride deoxyscytalidin. 5-Hydroxylation of deoxyscytalidin occurs prior to ring contraction in the zopfiellin pathway of Diffractella curvata. In Scytalidium album, 6-hydroxylation – confirmed as being catalysed by the α-ketoglutarate dependent oxidoreductase ScyL2 – converts deoxyscytalidin to scytalidin, in the final step in the scytalidin pathway. Feeding scytalidin to a zopfiellin PKS knockout strain led to the production of the nonadride castaneiolide and two novel ring-open maleidrides.

Graphical abstract: Uncovering biosynthetic relationships between antifungal nonadrides and octadrides

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Article information


Submitted
05 Aug 2020
Accepted
28 Sep 2020
First published
07 Oct 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Uncovering biosynthetic relationships between antifungal nonadrides and octadrides

K. M. J. de Mattos-Shipley, C. E. Spencer, C. Greco, D. M. Heard, D. E. O'Flynn, T. T. Dao, Z. Song, N. P. Mulholland, J. L. Vincent, T. J. Simpson, R. J. Cox, A. M. Bailey and C. L. Willis, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC04309E

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