Investigating the Toxicity of the Aeruginosin Chlorosulfopeptides by Chemical Synthesis

Abstract

Harmful algal blooms are becoming more prevalent all over the world, and identification and mechanism of action studies of the responsible toxins serve to protect ecosystems, livestock and humans alike. In this study, the chlorosulfopeptide aeruginosin 828A, which rivals in crustacean toxicity the well-known toxin microcystin LR, has been synthesized for the first time. In addition, three congeners with different permutations of the chloride and sulfate groups have been prepared, thereby allowing for toxicity studies without the risk of contamination by other natural toxins. Toxicity assays with the sensitive crustacean Thamnocephalus platyurus demonstrated that the introduction of a sulfate group leads to pronounced toxicity, while NMR spectroscopic evidence suggests that the chloride substituent modulates the conformation, which influences protease inhibitory activity.

Stereochemistry and biological activity of chlorinated lipids: a study of danicalipin A and selected diastereomers

“… 4 , 5 Halogenation is known to influence electronic properties, lipophilicity, and metabolic stability of bioactive molecules. 6 , 7 Additional subtle effects may be manifest in conformational preferences 8 especially in aliphatic systems as notably highlighted by Hoffmann, 8 b O'Hagan, 8 c and more recently by Gademann. 8 d We were interested in the question: Do configurational isomers 2 and 3 ( Fig.…”

Microviridin 1777: A Toxic Chymotrypsin Inhibitor Discovered by a Metabologenomic Approach

“…The cytotoxicity of purified 1 was around five times greater than the extract, but remains roughly one order of magnitude weaker than other cyanobacterial toxins. [27][28][29][30][31][32][33][34][35][36][37] To understand the mechanism of action of microviridin 1777 (1), an enzyme assay with trypsin, chymotrypsin, and elastase was performed (Figure 4) using modified literature procedures. 31,45 Whereas only weak inhibition of trypsin could be observed (IC50 > 10 µM), microviridin 1777 (1)…”

“…24 These research tools have been particularly successful in the analysis of cyanobacterial extracts [25][26][27][28] recently highlighted by the global metabolomics study of Microcystis. 29 In the context of our work on new cyanobacterial toxins, [30][31][32][33][34][35][36] we have postulated that strong protease inhibitors can display biological effects beyond deterrence leading to fatal effects on grazers. Experimental support for this hypothesis is documented in a number of studies, [37][38][39][40] providing evidence that peptides from different classes such as cyanopeptolins and aeruginosins can display strong grazer toxicity.…”

“…Experimental support for this hypothesis is documented in a number of studies, [37][38][39][40] providing evidence that peptides from different classes such as cyanopeptolins and aeruginosins can display strong grazer toxicity. [31][32][33][34]41 In order to further corroborate the production of multiple toxins by cyanobacteria, we were interested in potent protease inhibitors from other classes, which…”

Distribution and conservation of known secondary metabolite biosynthesis gene clusters in the genomes of geographically diverse Microcystis aeruginosa strains

“…Aeruginosins are linear non-ribosomal tetrapeptides characterised by a central L-2-carboxy-6-hydroxyoctahydroindole (L-Choi) moiety, a C-terminal arginine derivative (e.g. argininal, argininol, agmatine, 1-amidino-2-ethoxy-3-aminopiperidine) and an N-terminal hydroxyphenyl lactic acid or phenyl lactic acid group (Ersmark et al 2008;Scherer et al 2016). Most aeruginosins are potent inhibitors of serine proteases, including the human blood coagulation cascade enzyme thrombin and the digestive enzyme trypsin (Ersmark et al 2008).…”