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.
Highlights
Fungal maleidrides are an important family of polyketidederived secondary metabolites which exhibit a diversity of biological activities including as antifungal[1,2] and herbicidal[3,4] agents.[5]
This work categorically establishes the biosynthetic relationship between the nonadride scytalidin and the octadride zop ellin 15, via the shared nonadride intermediate; deoxyscytalidin
Deoxyscytalidin is the substrate for aKGdependent dioxygenase enzymes
Summary
Fungal maleidrides are an important family of polyketidederived secondary metabolites which exhibit a diversity of biological activities including as antifungal[1,2] and herbicidal[3,4] agents.[5]. In certain cases the relative and absolute stereochemistry of the maleidrides remain unknown, and various details of their biosynthesis are yet to be fully elucidated
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