Cyanopeptolins - cyanotoxins in the shadow of the famous microcystins – University of Copenhagen

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NaToxAq > Toxin of the week > Cyanopeptolins

11 September 2017

Cyanopeptolins - cyanotoxins in the shadow of the famous microcystins

Natural toxin

Cyanotoxins are a structurally diverse group of secondary metabolites often co-produced by various species of cyanobacteria. These metabolites can be classified by their toxic mode of action, including hepatoxins, neurotoxins, and dermal toxins. Other than the well-known microcystins, we know much less about the stability and potency of the many other cyanotoxins.

Cyanobacteria are present in many surface waters around the world and they can multiply rapidly when conditions are favourable. Along with these bloom events, the abundance of toxic cyanopeptides increases. However, the ecological reason for the production of cyanopeptides is still a puzzle to be solved.  As these cyanopeptides can become troublesome to human and ecological health, risk assessment for water quality management is necessary. Risk is defined as the product of potency of and exposure to a toxic compound – however, neither of these properties is well understood for most cyanopeptides.

In the scientific literature, many more studies focus on the class of microcystins compared to the other families of cyanotoxins including aeruginosin, microviridin, cyanopeptolin, microginin, anabaenopeptin, aerucyclamides (see Figure 1). Amongst those, cyanopeptolins are a class of cyanopeptides that act as enzyme inhibitors. While microcystins inhibit type 1 (IC50 = 1.7 nM) and type 2A (IC50 = 40 µM) phosohatases, cyanopeptolins inhibit proteases like trypsin (IC50 = 670 pM)1,2.  The very low effective inhibitory concentration (IC) suggest high potency of cyanopeptolins.

Figure 1. Number of search results in google scholar for the respective cyanopeptide class (search from 05 Sept 2017, excluding patents and citations).

The family of cyanopeptolins are non-ribosomal depsipeptides, i.e., with an ester bond as part of their backbone, that contain the structural moiety 3-amino-6-hydroxy-2-piperidone (AHP) that is indicative for this cyanopeptide family.3 The many variations of the other monomers make the class of cyanopeptolins structurally diverse (Figure 2). The cyclic structure, presence of D-amino acids, as well as non-standard amino acid make these compounds longer lived towards abiotic and biotic transformation reactions.

Figure 2. Molecular structure of Cyanopeptolin 1020 with the characteristic 3-amino-6-hydroxy-2-piperidone, AHP, moiety. Colored elements and listed abbreviations indicate structural variants of identified cyanopeptolins.

SMILES: CCCCCC(=O)NC(CCC(=O)O)C(=O)NC1C(OC(=O)C(NC(=O)C(N(C(=O)C(N2C(CCC(C2=O)NC(=O)C(NC1=O)CCCN=C(N)N)O)CC3=CC=CC=C3)C)CC4=CC=C(C=C4)O)C(C)C)C

References:
1. Gademann et al., 2010: Multiple Toxin Production in the Cyanobacterium Microcystis: Isolation of the Toxic Protease Inhibitor Cyanopeptolin 1020. J. Nat. Prod. 73, 980–984. http://dx.doi.org/10.1021/np900818c

2. Honkanen et al., 1990: Characterization of microcystin-LR, a potent inhibitor of type 1 and type 2A protein phosphatases. J Biol Chem.  15;265(32): 19401-4. http://www.jbc.org/cgi/content/short/265/32/19401

3. Welker & von Döhren. 2006: Cyanobacterialpeptides Nature’s own combinatorial biosynthesis. FEMS Microbiol Rev 30 530-563. https://doi.org/10.1111/j.1574-6976.2006.00022.x