Scalable biosynthesis of the seaweed neurochemical kainic acid

Kainic acid, the flagship member of the kainoid family of natural neurochemicals, is a widely used neuropharmacological agent that helped unravel the key role of ionotropic glutamate receptors, including the kainate receptor, in the central nervous system. Worldwide shortages of this seaweed natural product in 2000 prompted numerous chemical syntheses that now number in excess of 70, including scalable preparations with as few as six‐steps. Herein we report the discovery and characterization of the concise two‐enzyme biosynthetic pathway to kainic acid from L‐glutamic acid and dimethylallyl pyrophosphate in red macroalgae and show that the biosynthetic genes are co‐clustered in genomes of Digenea simplex and the edible Palmaria palmata. Moreover, we applied a key biosynthetic α‐ketoglutarate‐dependent dioxygenase enzyme in a biotransformation methodology to efficiently construct kainic acid on the gram scale. This study establishes both the feasibility of mining seaweed genomes for their biotechnological prowess and the applicability of the genes as biocatalysts in the synthesis of fine chemicals.