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This study investigates the evolutionary history of ketosynthases (KSs) and chain length factors (CLFs), enzymes responsible for synthesizing bacterial aromatic polyketides. Using a protein language model-based algorithm called MAAPE, researchers traced these enzymes to a shared ancestral cluster, demonstrating common origin but distinct evolutionary trajectories influenced by coevolution and horizontal gene transfer. The findings provide insight into how these enzymes naturally optimized their functions over evolutionary time.
Why it matters
Understanding the evolutionary pathways of these biosynthetic enzymes could enable rational engineering of novel polyketides with improved properties, potentially leading to new antibiotics, anticancer agents, or other therapeutically valuable compounds. This knowledge bridges evolutionary biology with synthetic biology applications for drug development.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: The evolutionary processes of bacterial aromatic polyketide ketosynthases