Pritam Chattopadhyay

(1) Background: This study highlights the diversity and distribution of non-reducing polyketide synthases (NR-PKSs) in Ascomycota and their role in producing bioactive aromatic polyketides. (2) Methods: A reference dataset of non-NR-PKSs was compiled from published literature and cross-examined using NaPDoS2 and Kyoto Encyclopedia of Genes and Genomes Ortholog (KEGG KO) databases. Signature domains were validated through Pfam and CDD, while phylogenetic classification was conducted by comparing the dataset with the NaPDoS2 reference tree. Cluster support was derived from KEGG KO and homology-based modeling. Additionally, NR-PKS clade distribution across KEGG genomes was analyzed, and co-expression patterns were examined using STRING. (3) Results: This study identified nine distinct clades of NR-PKSs, six of which are supported by unique KEGG Orthology (KO) numbers. These clades are as follows: clade 1: polyketide synthase A (PksA, K15316); clade 2: fusarubinsynthase 1 (Fsr1); clade 3: white A (WA, K15321); clade 4: polyketide synthase citrinin (PksCT); clade 5: zearalenone synthase 1 (Zea1, K15417); clade 6: orsellinic acid synthase A (OrsA, K15416); clade 7: aurofusarin polyketide synthase A (AptA, K15317); clade 8: monodictyphenone polyketide synthase G (MdpG, K15415); and clade 9: bikaverin polyketide synthase (Bik1). The present investigation also reports incongruency in the distribution of different NR-PKSs and fungi phylogeny within the phylum Ascomycota. (4) Conclusions: The distribution of NR-PKSs in Ascomycota defies phylogenetic boundaries, reflecting the impact of horizontal gene transfer, gene loss, and ecological adaptation.