Automated structure prediction of trans-acyltransferase polyketide synthase products

Abstract

Bacterial trans -acyltransferase polyketide synthases ( trans -AT PKSs) are among the most complex known enzymes from secondary metabolism and are responsible for the biosynthesis of highly diverse bioactive polyketides. However, most of these metabolites remain uncharacterized, since trans -AT PKSs frequently Occur in poorly studied microbes and feature a remarkable array of non-canonical biosynthetic components with poorly understood functions. As a consequence, genome-guided natural product identification has been challenging. To enable de novo structural predictions for trans -AT PKS-derived polyketides, we developed the Trans -AT PKS Polyketide Predictor (TransATor). TransATor is a versatile bio- and chemoinformatics web application that suggests informative chemical structures for even highly aberrant trans -AT PKS biosynthetic gene clusters, thus permitting hypothesis-based, targeted biotechnological discovery and biosynthetic studies. We demonstrate the applicative scope in several examples, including the characterization of new variants of bioactive natural products as well as structurally novel polyketides from unusual bacterial sources.

Comparative genomics reveals complex natural product biosynthesis capacities and carbon metabolism across host‐associated and free‐living Aquimarina (Bacteroidetes, Flavobacteriaceae) species

“…B) containing seven BGCs exclusive to strains within the A. megaterium‐macrocephali‐atlantica group. These BGCs underly the assembly of the newly discovered trans ‐AT polyketide cuniculene (Helfrich et al ., ), whose bioactivity is yet to be established. Taken together, results on GFC partitioning within ‘PKSother’ clans A and B provide evidence for specialized natural product biosynthesis and conservation of BGCs within a narrow, phylogenetically coherent range of species within the Aquimarina genus.…”

“…Interestingly, within PKSother clan B are the BGCs involved with the biosynthesis of a novel polyketide named cuniculene, recently described for Aquimarina sp. Aq349 (Helfrich et al ., ). Cuniculene has a trans ‐AT PKS and ladderane‐type structure, the same class that was found, in this study, in the antiSMASH predictions for Aquimarina strains Aq349, AU58 and EL33.…”

“…EL33, Aq78, Aq107, Aq135 and Aq349 (Esteves et al ., ; Keller‐Costa et al ., , ) and the remainder originate from seawater, marine sediments and algae (Table ). Strain Aq349 is the source of the recently described trans ‐AT polyketide cuniculene (Helfrich et al ., ). Other notable strains analysed in this study are the above‐mentioned ESD causing agent strain I32.4 (Quinn et al ., ; Ranson et al ., ) and macroalgal bleaching agents Aquimarina sp.…”

“…5B) containing seven BGCs exclusive to strains within the A. megaterium-macrocephali-atlantica group. These BGCs underly the assembly of the newly discovered trans-AT polyketide cuniculene (Helfrich et al, 2019), whose bioactivity is yet to be established. Taken A. GCFs (n = 439) identified across seven major compound classes are represented after homology-based analysis of BGCs with BiG-SCAPE.…”

“…In recent years, the presence of such genes is being consistently detected in different Aquimarina strains via genome sequencing (Keller-Costa et al, 2016;Ranson et al, 2018;Hudson et al, 2019). Moreover, structure elucidation of cuniculene, the first trans-AT polyketide ever reported from Aquimarina, has just been achieved (Helfrich et al, 2019). In this context, this study benefits from recent advances in computational biology and in silico genome mining (Medema et al, 2015;Blin et al, 2017;Medema, 2018;Navarro-muñoz et al, 2018) to examine the abundance, diversity, phylogenetic relationships and co-occurrence networks of secondary metabolite biosynthetic gene clusters (BGCs) across all publicly available Aquimarina genomes as of February 25, 2019, substantially enlarging the known genetic space underlying natural product biosynthesis within the Bacteroidetes phylum.…”