Algal neurotoxin biosynthesis repurposes the terpene cyclase structural fold into an N -prenyltransferase

Significance Domoic acid is a neurotoxin produced by marine algae that readily bioaccumulates in shellfish with significant impacts for both human and animal lives. The first committed step of domoic acid biosynthesis is theN -prenylation ofl -glutamic acid catalyzed by DabA. By solving the crystal structure of DabA, we demonstrate that DabA repurposed the phylogenetically ubiquitous terpene cyclase fold to catalyze a rarer reaction,N -prenylation of a primary amine. These structural insights enabled the rational engineering of twoN -prenyltransferases to accept alternative prenyl donors. These results expand our understanding of the reaction scope catalyzed by terpene cyclase folds and will inform future domoic acid environmental monitoring efforts.