Nitrogen starvation of cyanobacteria results in the production of β-N-methylamino-L-alanine

β-N-methylamino-L-alanine, an unusual amino acid implicated in neurodegenerative disease, has been detected in cultures of nearly all genera of environmentally ubiquitous cyanobacteria tested. The compound is present within cyanobacterial cells in free and protein-associated forms, with large variations occurring in the concentration of these pools between species as well as within single strains. With a lack of knowledge and supporting data on the regulation of BMAA production and the role of this compound in cyanobacteria, the association between BMAA and cyanobacteria is still subject to debate. In this study we investigated the biosynthesis of BMAA in axenic non-diazotrophic cyanobacterial cultures using the stable isotope 15N. Nitrogen starvation of nutritionally replete cells resulted in an increase in free cellular 15N BMAA suggesting that BMAA may be the result of catabolism to provide nitrogen or that BMAA is synthesised to serve a functional role in the cell in response to nitrogen deprivation. The addition of NO3− and NH4+ to the culture medium following starvation resulted in a decrease of free cellular BMAA without a corresponding increase in the protein-associated fraction. The use of ammonia as a nitrogen source resulted in a more rapid reduction of BMAA when compared to nitrate. This study provides the first data regarding the regulation of intracellular BMAA concentrations in cyanobacteria with results conclusively showing the production of 15N BMAA by an axenic cyanobacterial culture. ► First report providing irrefutable evidence for the cyanobacterial origin of neurotoxic β-N-methylamino-L-alanine (BMAA). ► First report of the de novo synthesis of BMAA from provided labelled raw materials by an axenic cyanobacterial culture. ► First report on the environmental modulation of BMAA production by cyanobacteria.