Insight into the role of a trans-AT polyketide synthase in the biosynthesis of lankacidin-type natural products

Abstract

Modular polyketide synthases (type I PKSs) are biosynthetic assembly lines for synthesizing a diverse array of natural products. While most PKSs exhibit a linear module architecture, the PKS system for lankacidin-type natural products contains only five modules but carries out eight rounds of polyketide extension, challenging the collinearity rule. Here we show the distinct domain architecture of the polyketide synthase enzyme, CheC, which is central to chejuenolide biosynthesis. CheC not only dissociates from and interacts with both the preceding and succeeding PKS enzymes, creating two linear modules, but also independently assembles an unconventional module, facilitating multiple rounds of polyketide extension in the biosynthetic process. We also unveiled missing functions of certain redundant and absent domains within PKSs, fully elucidating the polyketide assembly process for lankacidin-like natural products. These findings not only reveal the biosynthetic pathway for lankacidin- and chejuenolin-type natural products but also enrich the diverse functions of PKSs, setting the stage for future rational design of PKSs. In vitro biosynthetic analysis reveals that a single trans-AT polyketide synthase (PKS) module iteratively enables five rounds of polyketide elongation and interacts with both the preceding and succeeding PKS enzymes to produce the 17-membered macrocyclic polyketide chejunolide.