Science 361, 1356–1358 (2018)

The neurotoxin domoic acid (DA) is produced by marine diatoms of the genus Pseudo-nitzschia, which can cause harmful algal blooms. Past work suggested glutamic acid and geranyl pyrophosphate as precursors of DA, but the proteins and transformations involved in its biosynthesis were not known. Using transcriptome sequencing to identify genes that were upregulated during growth with limited phosphate and increased carbon dioxide levels (conditions known to promote DA production), Brunson and McKinnie et al. have now elucidated the biosynthetic pathway of this environmental neurotoxin. Among the upregulated genes was a four-gene cluster encoding a predicted terpene cyclase (DabA), α-ketoglutarate-dependent dioxygenase (DabC), cytochrome P450 (DabD), and a hypothetical protein (DabB). In vitro reconstitution of these enzymes validated that DabA catalyzes N-geranylation of l-glutamate to form N-geranyl-l-glutamic acid (l-NGG), which is successively oxidized by DabD into 7′-carboxy-l-NGG and cyclized by DabC into isodomoic acid A. Although an enzyme responsible for the final isomerization step to DA was not identified in this study, the discovery of the other biosynthetic genes may help to better understand the conditions that promote algal blooms and monitor DA production capability during those events.

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