Genome-based discovery of polyketides generated by trans-acyltransferase polyketide synthases

Polyketide synthases (PKSs) are multienzyme complexes that produce bioactive compounds with applications in medicine and agriculture. This review focuses on the genome-guided discovery of polyketides synthesized by trans-acyltransferase (trans-AT) PKSs, which, compared with the more prevalent cis-AT PKS counterparts, introduce distinct and complex chemical features that may entail specialized biological activities. With the rapid expansion of genomic data and abundance of trans-AT PKS biosynthetic gene clusters (BGCs), it is crucial to prioritize these clusters for experimental characterization based on their potential to produce novel molecules with valuable bioactivities. We outline methodologies for identifying BGCs, predicting the polyketide structure using ketosynthase phylogeny, and detail strategies for prioritizing BGCs for experimental characterization. We further describe approaches for producing extracts containing the target polyketide in the laboratory, as well as methods for its identification, isolation, and structural characterization. We expect that the strategies discussed in this review will accelerate the discovery of novel trans-AT PKS products, unlocking their potential to drive advancements in drug discovery.