Imagine cyanobacteria as microscopic engineers that have been producing molecules with protective, survival, communication and competitive properties for millions of years. Many of these molecules, which we call natural products, have already been discovered by the scientific community and are used in a wide variety of applications: from the naval industry to pharmaceuticals and medicine.

This time, these “blue engineers” surprised CIIMAR researchers by revealing a new biochemical “trick”: the ability to add phosphate groups to cyanobactins – one of the most studied families of peptides with therapeutic potential in cyanobacteria – in a process known as phosphorylation, which had never before been observed in this family of compounds.

The potential of this discovery, although highly specific to the chemistry of natural products, translates very simply: it opens up a whole new horizon of possibilities for marine biotechnology, especially for the development of future drugs.

The study, now published in the journal Nature Communications, has Raquel Castelo-Branco, a researcher in the CIIMAR Cyanobacterial Natural Products group, as its first author, and was coordinated by the group’s principal investigator Pedro Leão, in collaboration with David Fewer of the University of Helsinki.

The new molecular “tool”

During Raquel Castelo-Branco’s PhD in Marine Biotechnology and Aquaculture at the Faculty of Sciences of the University of Porto (FCUP), bioinformatic analysis of cyanobacterial genomes from the LEGE (CIIMAR) and UHCC (University of Helsinki) collections revealed an unexpected clue: an enzyme with an “extra” domain that would allow it to perform phosphorylation.

Raquel Castelo-Branco is surprised by the simplicity of the discovery: “The most fascinating thing was to see how a small genetic sequence identified in the genome led to the discovery of a new modification in cyanobactin.”

It is a rare enzyme that combines this new possibility of phosphorylation with the already known biosynthetic pathways of cyanobactins. In short, this combination, never before observed, functions as a “new module” in the biotechnology toolbox: it allows cyanobacteria themselves to produce phosphorylated molecules naturally and sustainably, without the need for laboratory chemistry.

“It is a perfect example of how genomics can reveal new biochemical functions hidden in nature,” explains the CIIMAR researcher.

But why is this important?

Phosphorylation is a very common biochemical process in cells, in which a phosphate group is added to other molecules. In proteins, this modification normally acts as a temporary regulatory mechanism, functioning as a ‘switch’ that turns their activity on or off depending on the cell’s needs. However, the phosphorylation discovered in this study is different. Instead of being a transient signal, it is a stable chemical modification, installed by a specialised enzyme during the biosynthesis of cyanobactins. This phosphorylation is part of the final structure of the molecule itself, giving it unique properties and potentially new biological functions.

“Phosphorylation is a common modification in proteins, but extremely rare in the small specialised molecules we normally call ‘natural products’,” explains Raquel Castelo-Branco. The fact that cyanobacteria do this transcends all scientific knowledge documented to date and opens the door to new strategies for the sustainable synthesis of phosphorylated compounds.

In the future, researchers plan to build a diverse library of peptides, which will be phosphorylated by this new enzyme, allowing them to explore its therapeutic potential in different areas, from oncology to regenerative medicine.

“We believe that this work could pave the way for the development of a library of phosphorylated peptides with anti-cancer, anti-bacterial and anti-viral potential,” adds the researcher. “Nature continues to be an inexhaustible source of inspiration for creating more sustainable and innovative products,” concludes the CIIMAR researcher.