The biosynthesis of the eagle-killing toxin has been elucidated

The researchers identified a pathway for biosynthesis for a cyanobacterial toxin known as aectoctonotoxin (AETX). The toxin is highly brominated, which is rare in both cyanobacteria and freshwater media.

In 1994, scientists discovered a neurological disease in bald eagles that causes damage to the brain and spinal cord. It took researchers more than a quarter of a century to link the disease to AETX, which is produced by cyanobacteria that grow on invasive aquatic plants Hydrilla verticillata (Science 2021, DOI: 10.1126 / science.aax9050). Although they identified a cluster of genes responsible for the synthesis, they did not figure out the path.

Bradley S. Moore and his colleagues at the University of California, San Diego studied polybromed natural products in salt water. They were intrigued by AETX, which contains five bromines and nitriles, and they wanted to find out how they do it.

They found that AETX comes from two tryptophan building blocks that are separately decorated before the connection (J. Am. chem. Sat. 2022, DOI: 10.1021 / jacs.1c12778). Flavin-dependent halogenase (AetF) adds bromine to tryptophan as a first step in both areas of the pathway. In one branch of the pathway, AetF adds a second bromine, and then another enzyme, called AetD, converts the tryptophan side chain to nitrile. In another compartment the enzymes remove the alanyl group and add two bromines. Finally, a fifth separate enzyme binds two indoles in modified tryptophan.

AetF and AetD are unusual enzymes. Most flavin-dependent halogenases work with a partner protein to regenerate cofactors, but AetF “doesn’t need a partner because it has that ability to reductase in the same protein,” Moore says. This may make AetF attractive to the industry as a biocatalyst. “If you can have one enzyme versus two, it’s much easier,” Moore says.

AetD left Moore and his colleagues trying to figure out how one enzyme could convert an alanyl group to a nitrile. “We still need to know more about how this enzyme works and what it’s capable of,” says Moore. “It does much more than a synthetic chemist can do in a chemical reaction with a single reaction step.”

“AetF is very interesting because it eliminates the need to add a separate reductase to regenerate cofactors,” writes Jared C. Lewis, a professor of chemistry at Indiana Bloomington University who studies biocatalysis. “I was most intrigued by the nitrile formation catalyzed by AetD. It may be useful for biocatalysis, but the enzyme that catalyzes it will almost certainly be interesting simply because of the nature of the bonds that must be formed and broken in this transformation. ” The biosynthesis of the eagle-killing toxin has been elucidated

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