Uncovering Biosynthetic Relationships Between Antifungal Nonadrides and Octadrides

Kate M J De Mattos-Shipley, Catherine E Spencer, Claudio Greco, David M Heard, Daniel E O'Flynn, Trong T Dao, Zhongshu Song, Nicholas P Mullholland, Jason L Vincent, Thomas J Simpson, Russell J Cox, Andrew M Bailey, Chris L Willis

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Pages (from-to)11570-11578
Number of pages9
JournalChemical Science
Volume11
Early online date7 Oct 2020
DOIs
Publication statusE-pub ahead of print - 7 Oct 2020

Structured keywords

  • Bristol BioDesign Institute

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