There is no doubt that microcystins belong to the most potent toxins in aquatic environments. However, this “toxic power” does not necessarily reflect the primary function of microcystins for its producing cell; in particular as critical amounts are typically not released into the water body by exponentially growing cells. There is a general concern whether microbial antibiotics do play a major role in defence in their respective ecosystems, instead there is more and more evidence for principal roles of small molecules in cell-cell communication rather than in antibiosis 
. The results of this study indicate an entirely new function of a secondary metabolite and a surprisingly close connection of microcystin to the primary metabolism of cyanobacteria.
Binding of microcystin to cellular components has been postulated earlier. Jüttner and Lüthi observed a binding of the toxin to cyanobacterial antennae proteins 
, while Vela and coworkers reported the association of microcystin with a set of proteins in vitro
and in vivo 
. However, in these studies the binding was considered as unspecific and non-covalent, and not linked to a physiological function. Our data reveal a specific and covalent interaction of microcystin with a subset of proteins resulting in their altered accumulation under different light or redox conditions. These different findings, however, do not necessarily contradict each other. In order to establish a covalent bond, microcystin has to build up a non-covalent interaction first. Under high light and oxidative stress conditions, this non-covalent interaction is then strengthened by covalent interactions of cysteines and the N-methyldehydroalanine position of microcystin. Though we are far from understanding the role(s) of microcystin, an increasing number of facts indicate an intracellular function of microcystin related to oxidative stress: (1) the increased transcription of mcy
mRNA under high light and iron-deficient conditions 
; (2) the remarkable overlap of proteins affected by the loss of microcystin with known redox-sensitive proteins in cyanobacteria; (3) the binding of microcystin to cysteines that are sensitive to redox changes; 4) the strong increase of microcystin binding to proteins under high light and oxidative stress conditions; and 5) the increased sensitivity of microcystin-deficient mutants under high light and oxidative stress conditions.
The observed microcystin binding to specific proteins in cells of the natural producer Microcystis
could possibly precede dimerization of cysteines and thus detain enzymes from conformational changes or even loss of their catalytic activity. Remarkably, the Calvin cycle is represented by several of its enzymes. The list of individual proteins almost completely overlaps with the list of known thioredoxin interaction partners of the Calvin cycle 
. With RbcL, RbcS and Prk at least three of the proteins were shown to directly interact with microcystin (see ). RbcL is known as a “cysteine sensitive” protein on the basis of its inactivation by thiol-directed reagents such as p-chloromercuribenzoate 
. For chloroplast Prk it could be shown that formation of a disulfide bond can even physically block the enzyme active site 
. The CP12 protein which was also found to be differentially expressed in wild type and mutant cells shows a redox-dependent binding to Calvin cycle enzymes in cyanobacteria as well as in chloroplasts 
. With glutathione reductase, another microcystin binding partner fits well into the general redox context. Future studies have to show the individual impact of microcystin on the expression, stability and activity of as many Microcystis
proteins as possible. This will allow us to integrate microcystin into the bioenergetic context and to interpret the phenotype of microcystin-deficient mutants under high light and conditions triggering oxidative stress.
A role of microcystin as protein-modulating metabolite and protectant against oxidative stress as suggested in our study could be the primary and original function of this secondary metabolite which would explain why probably all ancestral cyanobacteria produced these heptapeptides 
. The selective loss of the biosynthetic genes could be related to the enormous costs that are associated with the maintenance and activity of the giant gene cluster and the corresponding enzymatic complex. Possibly, the loss of microcystin biosynthesis was compensated by the evolution of other traits for the protection against oxidative stress. Considering RbcL as a major target, its enclosure in carboxysomes during the later cyanobacterial radiation could have made some of the protective mechanisms against oxidative stress dispensable. Still, microcystin production is very widespread among highly diverse bloom-forming species of cyanobacteria. The retention of microcystin in this environmentally successful group of cyanobacteria could thus relate to the specific lifestyle and the niche adaptation of these cyanobacteria, since in the bloom situation they are exposed to extremely high irradiances and oxygen over-saturation.
The data obtained in this study immediately raise the question whether non-toxic Microcystis
strains have evolved other mechanisms to compensate for the lack of microcystin or if these strains have indeed disadvantages under conditions triggering ROS development. However, if we compare the different strains we have to consider both the high costs of microcystin production and the potential benefit as postulated in this study. Recent studies comparing toxic and non-toxic Planktothrix
strains revealed that microcystin producing strains were clearly winning out against non-toxic strains when environmental conditions were limiting growth 
. Although this study supports a general impact of microcystin on the fitness of the producing cyanobacteria, it did not include conditions causing oxidative stress. Remarkably, this and other studies observed a decrease in microcystin quota per cell in the late exponential growth phase. In the light of the findings of the present study this decrease could be related to an increase in microcystin binding to proteins in senescent cultures that are accumulating ROS. In another study, Kardinaal and co-workers have looked at the competition for light between toxic and nontoxic strains of Microcystis
. Here, the toxic strains were in disadvantage; however, the light conditions used were not in the range typically causing oxidative stress 
. In order to translate the findings in our study to field situations thus thorough competition experiments are needed that compare the fitness of wild type and microcystin deficient mutant strains under oxidative stress conditions.