Abstract
Paralytic shellfish poisoning toxins (PSTs) are a family of more than 30 natural alkaloids synthesized by dinoflagellates and cyanobacteria whose toxicity in animals is mediated by voltage-gated Na+ channel blocking. The export of PST analogues may be through SxtF and SxtM, two putative MATE (multidrug and toxic compound extrusion) family transporters encoded in PSTs biosynthetic gene cluster (sxt). sxtM is present in every sxt cluster analyzed; however, sxtF is only present in the Cylindrospermopsis-Raphidiopsis clade. These transporters are energetically coupled with an electrochemical gradient of proton (H+) or sodium (Na+) ions across membranes. Because the functional role of PSTs remains unknown and methods for genetic manipulation in PST-producing organisms have not yet been developed, protein structure analyses will allow us to understand their function. By analyzing the sxt cluster of eight PST-producing cyanobacteria, we found no correlation between the presence of sxtF or sxtM and a specific PSTs profile. Phylogenetic analyses of SxtF/M showed a high conservation of SxtF in the Cylindrospermopsis-Raphidiopsis clade, suggesting conserved substrate affinity. Two domains involved in Na+ and drug recognition from NorM proteins (MATE family) of Vibrio parahaemolyticus and V. cholerae are present in SxtF/M. The Na+ recognition domain was conserved in both SxtF/M, indicating that Na+ can maintain the role as a cation anti-transporter. Consensus motifs for toxin binding differed between SxtF and SxtM implying differential substrate binding. Through protein modeling and docking analysis, we found that there is no marked affinity between the recognition domain and a specific PST analogue. This agrees with our previous results of PST export in R. brookii D9, where we observed that the response to Na+ incubation was similar to different analogues. These results reassert the hypothesis regarding the involvement of Na+ in toxin export, as well as the motifs L398XGLQD403 (SxtM) and L390VGLRD395 (SxtF) in toxin recognition.
Highlights
Cyanobacteria are a biochemically and morphologically diverse clade of photosynthetic bacteria, with major environmental and economic roles
In this study we developed a different approach to understand why there is more than one copy of putative transporter proteins in the sequenced sxt clusters, considering previous data on PST profiles in cyanobacteria and the export of toxins in R. brookii D9
SxtM amino acid sequences from all PSTs-producing cyanobacteria and V. cholerae (VC), we identified that the motifs characterized as Na+ (G184KFGXP189) and drug (L381XGXXD386) recognition sites were conserved in SxtF and SxtM (Figure 3)
Summary
Cyanobacteria are a biochemically and morphologically diverse clade of photosynthetic bacteria, with major environmental and economic roles They are main primary producers in marine and freshwater ecosystems, key biocatalysts in the N2 cycle [1] and some are capable of producing toxins. Toxin production can present waterborne health hazards for humans and animals. This has become of particular interest lately, due to the proliferation and dominance of harmful blooms of cyanobacteria; a result of the increase of eutrophication and climate change among others [2]. STX and its analogues (more than 30) have been detected in filter-feeding bivalve mollusks In humans, these toxins cause paralytic shellfish poisoning (PSP). STX has been shown to target voltage-gated potassium [5] and calcium [6] ion channels
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