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Fatty acid incorporation and modification in cyanobacterial natural products

Periodic Reporting for period 2 - FattyCyanos (Fatty acid incorporation and modification in cyanobacterial natural products)

Reporting period: 2019-07-01 to 2020-12-31

We currently know that cyanobacteria have the genetic information to produce a multitude of yet-unknown natural products. The same genetic information also tells us that a large fraction of those natural products will feature a fatty acid-derived moiety, intact or modified. Finding the natural products associated with these hidden genetic blueprints is not straightforward and is a major challenge in contemporary natural products chemistry. Tackling this issue brings with it the potential to reveal new chemical structures: these can inspire chemists due to their complexity, illuminate chemically-mediated ecological interactions, become future drugs or pharmacological probes. Elucidating the biosynthesis of such fatty acid-incorporating natural products can also reveal new enzymatic function, which in turn can lead to the development of future biocatalysts or add to the metabolic engineer toolbox.
With this in mind, the FattyCyanos project aims to:
A) develop a method to swiftly uncover fatty acid incorporating natural products in cyanobacteria and apply it to large number of cyanobacterial strains. This method should work both with and without previous information on the genetic capacity of the target cyanobacterium to produce such compounds.
B) study the biosynthesis of selected fatty acid-incorporating and -modifying natural products, to reveal unusual biocatalytic transformations and the enzymes that catalyze them.
We have successfully developed the proposed method for fatty acid-incorporating metabolite discovery and have found several new natural products from only a couple of cyanobacteria. Some of these compounds are structurally unique, highlighting the potential of cyanobacteria for the discovery of novel natural products.

Furthermore, we have studied the biosynthesis of the bartolosides and revealed a biocatalytic transformation, mediated by the enzyme BrtB, which was until then only known in synthetic chemistry. This enzymatic reaction is a new type of biological esterification in which the fatty acids are esterified to a halogenated carbon. Most strikingly, the fatty acids react as free carboxylates and therefore bypass what was thought was a universal requirement: fatty acid activation.

Finally, we have critically reviewed the literature on the alkylresorcinol-type of fatty acid-incorporating metabolites. We looked into the entire diversity of these compounds in cyanobacteria and identified opportunities for discovery of new metabolites and enzymes.
The method developed in the FattyCyanos project extends the number of strategies for natural product discovery in the metabolically-rich cyanobacteria. With this method in hands, we will now be able to screen a large number of strains and gain access to target compounds for isolation. Judging from our progress so far, with three families of compounds uncovered by this method in just two tested cyanobacteria, we expect that we will be able to reveal multiple new-to-science natural products and their associated biological activities.

Our discovery of BrtB and of its unprecedented reactivity, will enable additional explorations of the chemical and biosynthetic space associated with members of this fatty acid-acting enzyme class. Furthermore, our continuing biosynthesis studies on selected fatty acid incorporating metabolites is expected to reveal new biochemical transformations and new enzymes.

Our findings to date and anticipated future discoveries will overall lead to a better understanding of the utilization and modification of fatty acids in cyanobacterial secondary metabolism and facilitate natural products discovery efforts in these organisms.