Anabaenopeptins are a diverse family of cyclic hexapeptide protease inhibitors produced by cyanobacteria that contain a conserved ureido bond and D-Lys moiety. Here we demonstrate that anabaenopeptins are assembled on a nonribosomal peptide synthetase enzyme complex encoded by a 32 kb apt gene cluster in the cyanobacterium Anabaena sp. strain 90. Surprisingly, the gene cluster encoded two alternative starter modules organized in separate bimodular proteins. The starter modules display high substrate specificity for L-Arg/L-Lys and L-Tyr, respectively, and allow the specific biosynthesis of different anabaenopeptin variants. The two starter modules were found also in other Anabaena strains. However, just a single module was present in the anabaenopeptin gene clusters of Nostoc and Nodularia, respectively. The organization of the apt gene cluster in Anabaena represents an exception to the established colinearity rule of linear non-ribosomal peptide synthetases.
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