Giant Polyketide Synthases Biosynthesize a Marine Polyether Biotoxin

Abstract Prymnesin toxins were probably the direct cause of the environmental catastrophe in the Oder river in 2022. They belong to the so‐called ladder polyethers, which are among the most toxic non‐proteinogenic substances and have caused a whole series of food poisoning in humans and numerous other incidents of fish deaths. Despite massive efforts, the enzymatic machinery has remained enigmatic. In a recent study, researchers at the Scripps Institution of Oceanography and the University of California, San Diego, have uncovered the initial mechanisms by which algae produce these toxins. Crucial to the breakthrough was the methodological advance in sequencing and assembly that allowed the identification and analysis of the largest polyketide synthase (PKS) known to date, named PKZILLA‐1 and PKZILLA‐2, which enabled, among other things, the confirmation and elucidation of stereocenters. Thus, further investigations into the biosynthesis and other aspects of these highly toxic substances are made possible, which could perhaps make these ′biblical plagues′ predictable.