Redundant synthesis of a conidial polyketide by two distinct secondary metabolite clusters in Aspergillus fumigatus

Abstract

Summary Filamentous fungi are renowned for the production of bioactive secondary metabolites. Typically, one distinct metabolite is generated from a specific secondary metabolite cluster. Here, we characterize the newly described trypacidin (tpc) cluster in the opportunistic human pathogen Aspergillus fumigatus. We find that this cluster as well as the previously characterized endocrocin (enc) cluster both contribute to the production of the spore metabolite endocrocin. Whereas trypacidin is eliminated when only tpc cluster genes are deleted, endocrocin production is only eliminated when both the tpc and enc non-reducing polyketide synthase-encoding genes, tpcC and encA, respectively, are deleted. EncC, an anthrone oxidase, converts the product released from EncA to endocrocin as a final product. In contrast, endocrocin synthesis by the tpc cluster likely results from incomplete catalysis by TpcK (a putative decarboxylase), as its deletion results in a nearly 10-fold increase in endocrocin production. We suggest endocrocin is likely a shunt product in all related non-reducing polyketide synthase clusters containing homologues of TpcK and TpcL (a putative anthrone oxidase), e.g. geodin and monodictyphenone. This finding represents an unusual example of two physically discrete secondary metabolite clusters generating the same natural product in one fungal species by distinct routes.

Characterization of Aspergillus fumigatus Isolates from Air and Surfaces of the International Space Station

“…The combined analysis of CEA10, ISSFT-021, and IF1SW-F4 identified 1,578 variants in comparison with Af293 within the boundaries of the 26 SM gene clusters, and 504 of these variants were predicted to result in nonsynonymous substitution in an SM cluster gene (see Data Set S1). Importantly, our analysis corroborated the previously published point mutation R202L in FtmD (Afu8g00200), which results in loss of fumitremorgin production in Af293 (35), as well as the previously described frameshift mutation in TpcC in the CEA10 trypacidin cluster that leads to loss of function of the trypacidin polyketide synthase (36). A metabolite between pyripyropene A (peak no.…”

“…Interestingly, the more virulent ISS strains showed lower fumagillin production, suggesting that in vitro fumagillin production profiles may not be accurate predictors of virulence potential, based on our in vivo findings with the neutrophil-deficient larval zebrafish model. Monomethylsulochrin, a proposed precursor in the trypacidin pathway, is produced by both ISS strains and Af293 but not by CEA10, despite the ability of this strain to produce trypacidin (36). However, our study was insufficient to pinpoint which, if any, of the metabolites has influence on the increased virulence observed in the two ISS strains, and additional experiments will be necessary to identify the connection between increased virulence and specific metabolite production.…”

A Network Approach of Gene Co-expression in the Zea mays/Aspergillus flavus Pathosystem to Map Host/Pathogen Interaction Pathways

“…In this study, these genes were captured in the GEN. Also identified in the GEN were A. flavus genes related to transport signaling, such as COPI and COPII, as well as the ROS production genes in Z. mays AOX, peroxidase, and glutathione S -transferase. This matches previous studies reporting that mutations in lipoxygenases in Z. mays can have downstream effects on disease development and on aflatoxin production (Burow et al, 1997; Park et al, 2010; Scarpari et al, 2014; Throckmorton et al, 2016). Additionally, the GEN developed in this study revealed that several genes involved in ethylene induction are correlated with multiple A. flavus genes, exposing another facet of the interaction between A. flavus and Z. mays .…”

Secondary metabolite arsenal of an opportunistic pathogenic fungus

“…Another spore pigment, this compound is produced by a 13-gene BGC [32,64]. The endocrocin and trypacidin BGCs show redundancy as both synthesize the spore pigment endocrocin [32]. Trypacidin is known and named for its antiprotozoal (e.g.…”