The evolutionary processes of bacterial aromatic polyketide ketosynthases

Background: The biosynthesis of bacterial aromatic polyketide polyketides (type II polyketides, T2PKs) employs a single set of catalysts (ketosynthases, KSs or KS, with chain length factors, CLFs or KS{beta}) and iteratively assembles a carbon backbone with precise chain length control. Considering the increasing number of T2PKs discovered in laboratory settings, it is necessary to understand the evolution trajectories of KSs and CLFs. Results: We employed our recently developed algorithm, MAAPE, based on large protein language model (PLM) to glean insights into the evolution process of KSs and CLFs. Our findings indicated the evolutionary history of KS and CLF domains from bacterial T2PKSs and identified a shared ancestral cluster (Cluster A), supporting a common origin. Despite structural homology, KSs and CLFs followed distinct evolutionary paths, shaped by coevolution and early horizontal gene transfer. Conclusions: Understanding the evolutionary lineage of these enzymes will illuminate the natural optimization processes of their functions and present opportunities for the rational design of novel polyketides with enhanced efficacy.