Evolutionary Histories of Type III Polyketide Synthases in Fungi

Abstract

Type III polyketide synthases (PKSs) produce secondary metabolites with diverse biological activities, including antimicrobials. While they have been extensively studied in plants and bacteria, only a handful of type III PKSs from fungi has been characterized in the last 15 years. The exploitation of fungal type III PKSs to produce novel bioactive compounds requires understanding the diversity of these enzymes, as well as of their biosynthetic pathways. Here, phylogenetic and reconciliation analyses of 522 type III PKSs from 1,193 fungal genomes revealed complex evolutionary histories with massive gene duplications and losses, explaining their discontinuous distribution in the fungal tree of life. In addition, horizontal gene transfer events from bacteria to fungi and, to a lower extent, between fungi, could be inferred. Ancestral gene duplication events have resulted in the divergence of eight phylogenetic clades. Especially, two clades show ancestral linkage and functional co-evolution between a type III PKS and a reducing PKS genes. Investigation of the occurrence of protein domains in fungal type III PKS predicted gene clusters highlighted the diversity of biosynthetic pathways, likely reflecting a large chemical landscape. Type III PKS genes are most often located next to genes encoding cytochrome P450s, MFS transporters and transcription factors, defining ancestral core gene clusters. This analysis also allowed predicting gene clusters for the characterized fungal type III PKSs and provides working hypotheses for the elucidation of the full biosynthetic pathways. Altogether, our analyses provide the fundamental knowledge to motivate further characterization and exploitation of fungal type III PKS biosynthetic pathways.

Expansion and Conservation of Biosynthetic Gene Clusters in Pathogenic Pyrenophora spp.

“…The majority of BGCs were represented by NRPSs and Ptt had a greater than expected number as indicated in a previous study for this barley pathogen [30]. Although T3PKS have been studied in Ptr and Ptt [45] we established for the first time that this predicted gene cluster is highly conserved between the three Pyrenophora species. T3PKS are distinct from iterative T1PKS as they are independent of acyl carrier protein (ACP) and act directly on acetyl CoA substrates [46].…”

Identification and Characterization of a New Type III Polyketide Synthase from a Marine Yeast, Naganishia uzbekistanensis

“…A phylogenetic analysis was performed on 755 representative PKSIII proteins from eukaryotes and bacteria, including functionally characterized enzymes known to accept a diversity of CoA thioester starter units and including the 552 genes discovered in the study of Navarro-Munoz and Collemare [ 43 ]. The maximum likelihood phylogenetic analysis of 755 PKS III sequences led to the distinction of three major branches ( Figure 1 ).…”

“…Among them, type III PKSs isolated from Aspergillus oryzae [ 38 , 39 , 40 ] and another from Aspergillus niger [ 41 ] have been characterized, as well as a type III PKS isolated from Sporotrichum laxum which appears to be involved in the production of spirolaxine, a potential drug candidate with anti- Helicobacter pylori activity [ 42 ]. A recent analysis reveals a total of 552 type III pks genes from 1193 fungal genomes (JGI Mycocosm) [ 43 ]. Only eleven type III PKSs have been biochemically characterized in fungal kingdom [ 43 ].…”

“…A recent analysis reveals a total of 552 type III pks genes from 1193 fungal genomes (JGI Mycocosm) [ 43 ]. Only eleven type III PKSs have been biochemically characterized in fungal kingdom [ 43 ]. Polyketides produced by fungal type III PKS are grouped into triketide pyrones, tetraketide pyrones and alkylesorcinols [ 25 ].…”

Selecting for useful properties of plants and fungi – Novel approaches, opportunities, and challenges

“…Large‐scale genomic studies are also needed to prioritize functional studies and avoid studying already characterized biosynthetic pathways (Bushley & Turgeon, 2010; Chooi & Tang, 2012; Navarro‐Muñoz & Collemare, 2020). With increased numbers of characterized pathways, we may be able to produce new‐to‐nature natural products, such as biosynthetic enzymes engineered to perform chemical reactions that are difficult to obtain synthetically due to their specificity (Fürtges, Obermaier, Thiele, Foegen, & Müller, 2019), or produce higher yields of potentially useful compounds (Rebets, Brötz, Tokovenko, & Luzhetskyy, 2014).…”