Predicting the chemical space of fungal polyketides by phylogeny-based bioinformatics analysis of polyketide synthase-nonribosomal peptide synthetase and its modification enzymes

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.

Chemical and Genetic Studies on the Formation of Pyrrolones During the Biosynthesis of Cytochalasans

“…α,β‐Hydrolases related to PyiE and ORFZ are commonly found encoded in fungal PKS‐NRPS biosynthetic gene clusters, especially those with a reductive release mechanism [17] . For example, the cytochalasin E (CcsE), [5a] fusarin (Fus2), [18a, 24] pseurotin (PsoG), [18c] and phomacin (SnoG) [25] gene clusters all encode homologous α,β‐hydrolases.…”

“…Hydrolytic enzymes similar to PyiE, and its ACE1 homolog ORFZ, are encoded in the BGC of all known cytochalasans, [17] as well as in other BGC which encode the biosynthesis of compounds such as fusarin C where the PKS‐NRPS has a reductive release mechanism [18] . However, the precise function of these hydrolytic enzymes remains unknown.…”

Molecular basis for two stereoselective Diels-Alderases that produce decalin skeletons

“…It is likely that substrates bind to the pocket in a similar way (tetramic acid-front and polyene-back orientation) and stereoselective [4+2] cycloadditions proceed. Recent phylogenetic analysis has suggested that approximately 100 sequences are potentially involved in DP biosynthesis 40 . Therefore, this group of enzymes widely found in Ascomycota fungi would be an attractive target for structure-function relationship studies, providing key structural features to determine the stereoselectivity of these reactions.…”

“…1b) and even an unidentified metabolite (2 S ,3 R ,8 R ,11 S ). Recent phylogenetic analysis suggested that approximately 100 sequences are potentially involved in DP biosynthesis 49 . Therefore, this group of enzymes, which is widespread in Ascomycota fungi, are attractive targets for structure–function relationship studies, providing key structural features for determining the stereoselectivity of these reactions.…”

Cyanobacteria and Eukaryotic Microalgae as Emerging Sources of Antibacterial Peptides

“…In addition, vehicle degradation may sustain or control a gradual delivery of the peptide at the right site [ 65 , 66 , 67 , 68 ]. A greater decrease in the number of peptides entering the pipeline for peptide development is achieved by in silico selection of new and improved prediction tools for candidate selection based on an expected higher effectiveness or decreased toxicity [ 69 , 70 , 71 , 72 , 73 ].…”