TY - JOUR

T1 - Uncovering biosynthetic relationships between antifungal nonadrides and octadrides

AU - de Mattos-Shipley, Kate M. J.

AU - Spencer, Catherine E.

AU - Greco, Claudio

AU - Heard, David M.

AU - O'Flynn, Daniel E.

AU - Dao, Trong T.

AU - Song, Zhongshu

AU - Mulholland, Nicholas P.

AU - Vincent, Jason L.

AU - Simpson, Thomas J.

AU - Cox, Russell J.

AU - Bailey, Andrew M.

AU - Willis, Christine L.

N1 - Funding Information: We thank BBSRC (BB/K002341/1) and Syngenta for funding (KMJdMS, CG and ZS) and a PhD studentship BB/P504804/1 (CS). We are also grateful to MRC (MR/N029909/1) (funding for TTD) and EPSRC (EP/L015366/1), Bristol Chemical Synthesis Centre for Doctoral Training, which provided PhD studentships (DMH and DOF). We are also very grateful to BBSRC and EPSRC for funding instrumentation via the Bristol Centre for Synthetic Biology (BB/L01386X/1). Genome sequencing, the production of assembled dra genomes and RNA sequencing were all carried out at the DNA sequencing facility in the Biochemistry Department of Cambridge University. X-ray crystallography was carried out by Dr Hazel Sparkes, School of Chemistry, University of Bristol. In additional we are grateful to Dr Lauren Ray from Syngenta for her help and support during the Industrial placement for CS.

PY - 2020/11/14

Y1 - 2020/11/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85096302455&partnerID=8YFLogxK

U2 - 10.1039/d0sc04309e

DO - 10.1039/d0sc04309e

M3 - Article

VL - 11

SP - 11570

EP - 11578

JO - Chemical science

JF - Chemical science

SN - 2041-6520

IS - 42

ER -