Genomic insights into the biosynthesis and physiology of the cyanobacterial neurotoxin 2,4-diaminobutanoic acid (2,4-DAB)

Maria De Quintanilha Mantas, Peter B Nunn, Ziying Ke, Geoffrey A Codd, Daniel Barker

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Cyanobacteria are an ancient clade of photosynthetic prokaryotes, whose worldwide occurrence, especially in water, presents health hazards to humans and animals due to the production of a range of toxins (cyanotoxins). These include the sometimes co-occurring, non-encoded diamino acid neurotoxins 2,4-diaminobutanoic acid (2,4-DAB) and its structural analogue β-N-methylaminoalanine (BMAA). Knowledge of the biosynthetic pathway for2,4-DAB, and its role in cyanobacteria, is lacking. The aspartate 4-phosphate pathway is a known route of 2,4-DAB biosynthesis in other bacteria and in some plant species. Another pathway to 2,4-DAB has been described in Lathyrus species. Here, we use bioinformatics analyses to investigate hypotheses concerning 2,4-DAB biosynthesis in cyanobacteria. We assessed the presence or absence of each enzyme in candidate biosynthesis routes, the aspartate 4-phosphate pathway and a pathway to 2,4-DAB derived from S-adenosyl-Lmethionine(SAM), in 130 cyanobacterial genomes using sequence alignment, profile hidden Markov models, substrate specificity/active site identification and the reconstruction of gene phylogenies. In the aspartate 4-phosphate pathway, for the 18 species encodingdiaminobutanoate-2-oxo-glutarate transaminase, the co-localisation of genes encoding the transaminase with the downstream decarboxylase or ectoine synthase – often within hybrid non-ribosomal peptide synthetase (NRPS)-polyketide synthases (PKS) clusters, NRPS independent siderophore (NIS) clusters and incomplete ectoine clusters – is compatible with the hypothesis that some cyanobacteria use the aspartate 4-phosphate pathway for 2,4-DABproduction. Through this route, in cyanobacteria, 2,4-DAB may be functionally associated with environmental iron-scavenging, via the production of siderophores of the schizokinen/synechobactin type and of some polyamines. In the pathway to 2,4-DAB derived from SAM, eight cyanobacterial species encode homologs of SAM-dependent 3-amino-3-carboxypropyl transferases. Other enzymes in this pathway have not yet been purified or sequenced. Ultimately, the biosynthesis of 2,4-DAB appears to be either restricted to some cyanobacterial species, or there may be multiple and additional routes, and roles, for the synthesis of this neurotoxin.
Original languageEnglish
Article number112953
Number of pages14
Early online date29 Sept 2021
Publication statusPublished - 16 Nov 2021

Keywords / Materials (for Non-textual outputs)

  • cyanobacteria
  • cyanotoxin
  • 4-DAB
  • 4-diaminobutanoic acid
  • 4-diaminobutyric acid,
  • bioinformatics
  • diaminobutanoate-2-oxo-glutarate transaminase
  • diaminobutanoate decarboxylase
  • siderophore
  • ectoine


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