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 the year 2000 prompted numerous chemical syntheses, 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 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. Kainic acid is a marine natural product that has been used as an anthelmintic agent for centuries and, more recently, a neurological tool. Using a genomic sequencing approach, the genes responsible for the biosynthesis of kainic acid were discovered in two different seaweeds. In vitro characterization validated enzymatic activity and enabled gram‐scale production of kainic acid using a biotransformation approach.