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The best-known toxins made by cyanobacteria are the microcystins. Their toxicity to human beings and animals is primarily exerted in the liver, due to their high affinity to the liver-specific bile acid transport system. Detoxification of the microcystin molecule while retaining its selectivity would turn the hepatotoxin into a potential transporter for liver-active substances and allow for an organ-specific treatment. Cyano Biotech pursues the modification into a non-toxic variant by means of biocombinatorial changes and deletions of genes governing the microcystin biosynthesis in the producer organism. The basis for directed biocombinatorial changes to the genes is the knowledge of the gene cluster.
A 55 kb gene cluster in M. aeruginosa under the control of a bidirectional promoter encodes a hybrid system consisting of a nonribosomal peptide synthetase (NRPS), a polyketide synthase (PKS), and a number of tailoring enzymes responsible for the post PKS/NRPS modification steps. The chemical structure of microcystin is cyclo-(D-Ala-X- D-MeAsp-Z-Adda- D-Glu-Mdha), where X and Z represent variable amino acids at positions 2 and 4 of the molecule. Up to now the structures of more than 60 microcystins have been elucidated. The figure shows the biosynthesis of microcystin-LR, the most abundant variant, carrying a leucine at position 2 and an arginine at position 4.
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