25 June 2017

Microcystins – hepatotoxic cyclic peptides from blue-green algae (cyanobacteria)

Natural toxin

Cyanobacteria, belonging to the world’s oldest eukaryotic inhabitants, produce many secondary metabolites. Besides pigments and nutrient-sequestering substances, some strains produce toxic compounds: cyanotoxins. Amongst these, microcystins are the most extensively studied due to their frequent occurrence and high toxicity.

Fig.1 Cyanobacterial blooms and cyanobacteria producing cyanotoxins

Fig. 2 Structure of microcystin-LR. Click image for 3D structure

During cyanobacterial blooms (Fig. 1), a phenomenon occurring with increasing frequency and intensity due to anthropogenic eutrophication of surface water bodies and global warming, microcystins can be produced in large quantity with considerable impact on ecosystems, water-related tourism and drinking water quality.

Microcystins are produced by many widespread cyanobacterial genera (Fig. 1), which possess the necessary microcystin synthase genes, such as Microcystis, Planthothrix, Dolichospermum, Nodularia, or Oscillatoria.

Microcystins are cyclic non-ribosomal heptapeptides (Fig. 2) that interfere with cellular protein phosphatases PP1 and PP2A via the incorporated unusual amino acid ADDA ((all-S,all-E)-3-Amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid). Besides ADDA, other unusual, non-proteinogenic amino acids are incorporated.

The modular synthesis pathway of non-ribosomal peptide synthases can produce many structural variants of microcystins. More than 100 microcystin variants have been reported to date. Cyanobacterial strains generally produce around four microcystin congeners, mostly MC-LR, MC-RR and their desmethyl analogues, but production of up to 47 microcystin congeners per strain has been reported. Microcystin-LR (MC-LR, Fig. 2; PubChem CID: 445434) is the most studied microcystin among the different congeners, due to its ubiquity, abundance and toxicity. MC-LR-related toxic effects on liver were observed at nanomolar concentrations. Besides causing severe liver damage (hepatotoxin), microcystins may affect other organs including kidney, reproductive system, heart and lungs and may promote cancer, particularly after chronic low-dose exposures.

Fig. 3: Possible routes of exposure to cyanotoxins/microcystins

SMILES: C[C@H]1[C@@H](NC(=O)[C@@H](NC(=O)[C@H]([C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)C(=C)N(C(=O)CC[C@@H](NC1=O)C(=O)O)C)C)CC(C)C)C(=O)O)C)CCCN=C(N)N)/C=C/C(=C/[C@H](C)[C@H](CC2=CC=CC=C2)OC)/C

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