Abstract
Fungal polyketide synthase (PKS)–nonribosomal peptide synthetase (NRPS) hybrids are key enzymes for synthesizing structurally diverse hybrid natural products (NPs) with characteristic biological activities. Predicting their chemical space is of particular importance in the field of natural product chemistry. However, the unexplored programming rule of the PKS module has prevented prediction of its chemical structure based on amino acid sequences. Here, we conducted a phylogenetic analysis of 884 PKS–NRPS hybrids and a modification enzyme analysis of the corresponding biosynthetic gene cluster, revealing a hidden relationship between its genealogy and core structures. This unexpected result allowed us to predict 18 biosynthetic gene cluster (BGC) groups producing known carbon skeletons (number of BGCs; 489) and 11 uncharacterized BGC groups (171). The limited number of carbon skeletons suggests that fungi tend to select PK skeletons for survival during their evolution. The possible involvement of a horizontal gene transfer event leading to the diverse distribution of PKS–NRPS genes among fungal species is also proposed. This study provides insight into the chemical space of fungal PKs and the distribution of their biosynthetic gene clusters.
Highlights
Fungal polyketide synthase (PKS)–nonribosomal peptide synthetase (NRPS) hybrids are key enzymes for synthesizing structurally diverse hybrid natural products (NPs) with characteristic biological activities
To ensure the inclusion of meaningful samples for phylogenetic analysis, we excluded highly homologous hybrids found in the same species, which are strongly expected to synthesize the same PK intermediate, and included the recently characterized hybrids
Predicting the chemical structure of NPs using bioinformatics analysis based on genomic data is one of the biggest challenges in natural product research
Summary
Fungal polyketide synthase (PKS)–nonribosomal peptide synthetase (NRPS) hybrids are key enzymes for synthesizing structurally diverse hybrid natural products (NPs) with characteristic biological activities. Predicting their chemical space is of particular importance in the field of natural product chemistry. We conducted a phylogenetic analysis of 884 PKS–NRPS hybrids and a modification enzyme analysis of the corresponding biosynthetic gene cluster, revealing a hidden relationship between its genealogy and core structures. The wealth of fungal genome sequences deposited in public databases has enabled identification of biosynthetic gene clusters (BGCs) containing PKS genes using bioinformatics tools such as S MURF5 and A ntiSMASH6 Phylogenetic analysis of these PKSs, especially when focusing on the KS domain instead of the PKS itself, has Scientific Reports | (2020) 10:13556. To our knowledge, bioinformatics studies investigating the relationship between the genealogy and the chemical structure of PKs are s carce
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