The toxic effects of meta-tyrosine are related to its misincorporation into the proteome and to altered metabolism in cyanobacteria.

Cyanobacteria are prolific photosynthetic bacteria whose notable adaptability, coupled with a high metabolic versatility, enables them to thrive in diverse habitats across the globe. They play a key role in global primary production and nutrient cycling, but uncontrolled proliferation of certain species can harm aquatic life. Cyanobacterial blooms (cyanoblooms), triggered by factors such as nutrient influx, temperature, and light, significantly impact ecosystem dynamics and are intensifying due to global warming. Currently, there are no efficient means to mitigate these effects. Here, we show that meta-tyrosine (m-Tyr), a nonproteinogenic amino acid analog of aromatic amino acids (e.g., Phe and Tyr), is highly toxic to various cyanobacteria, whereas non-photosynthetic bacteria appear to be much less susceptible to m-Tyr. Examination of the molecular basis of m-Tyr toxicity in the model organism Synechocystis sp. PCC6803 is complex. Molecular and biochemical analyses indicate altered amino acid homeostasis in m-Tyr-treated cyanobacteria. Proteomic studies further showed that m-Tyr is misincorporated by phenylalanyl-tRNA synthetase (PheRS) into the Synechocystis proteome, particularly affecting ribosomal as well as photosynthetic-related proteins. Likewise, m-Tyr-treated Synechocystis exhibit altered translational and photosynthetic activities, which are tightly correlated with growth retardation and morphological changes at micromolar m-Tyr concentrations, and increased mortality at higher concentrations. These findings indicate that the toxicity of m-Tyr to Synechocystis results from a combination of cellular effects, including altered metabolism and its incorporation into the cyanobacterial proteome. This understanding might also contribute to the development of novel natural compounds for controlling harmful cyanoblooms.