Biosynthesis of the Isocoumarin Derivatives Fusamarins is Mediated by the PKS8 Gene Cluster in Fusarium

• Published in: Chembiochem : a European journal of chemical biology 2023-03, Vol.24 (6), p.e202200342-n/a
• Main Authors: Atanasoff‐Kardjalieff, Anna K., Seidl, Bernhard, Steinert, Katharina, Daniliuc, Constantin G., Schuhmacher, Rainer, Humpf, Hans‐Ulrich, Kalinina, Svetlana, Studt‐Reinhold, Lena
• Format: Article
• Language: English
• Subjects: Bioinformatics; Biosynthesis; Biosynthetic Pathways - genetics; Cytotoxicity; dihydroisocoumarins; Fusarium; Fusarium - genetics; Fusarium - metabolism; Fusarium fujikuroi species complex (FFSC); Genetics; heterochromatin; Histone methyltransferase; Malformation disease; Mangifera - genetics; Mangifera - metabolism; Mangoes; Metabolites; Metabolomics; Multigene Family; Mycotoxins; Polyketide synthase; Polyketide Synthases - genetics; Polyketide Synthases - metabolism; polyketides; Secondary metabolites; Seedlings; Toxicity
• ISSN: 1439-4227; 1439-7633; 1439-7633
• DOI: 10.1002/cbic.202200342

Fusarium mangiferae causes the mango malformation disease (MMD) on young mango trees and seedlings resulting in economically significant crop losses. In addition, F. mangiferae produces a vast array of secondary metabolites (SMs), including mycotoxins that may contaminate the harvest. Their production is tightly regulated at the transcriptional level. Here, we show that lack of the H3 K9‐specific histone methyltransferase, FmKmt1, influences the expression of the F. mangiferae polyketide synthase (PKS) 8 (FmPKS8), a so far cryptic PKS. By a combination of reverse genetics, untargeted metabolomics, bioinformatics and chemical analyses including structural elucidation, we determined the FmPKS8 biosynthetic gene cluster (BGC) and linked its activity to the production of fusamarins (FMN), which can be structurally classified as dihydroisocoumarins. Functional characterization of the four FMN cluster genes shed light on the biosynthetic pathway. Cytotoxicity assays revealed moderate toxicities with IC50 values between 1 and 50 μM depending on the compound. Fusaria are plant‐pathogenic fungi infecting several staple crops, and accumulating often toxic compounds during infection and hence threaten food security worldwide. The full chemical potential of these notorious pathogens is still elusive. Here, we characterized the previously cryptic PKS8 gene cluster and show that four genes are responsible for the biosynthesis of the dihydroisocoumarin derivates fusamarins with moderate cytotoxic effects.