Natural products from marine organisms have attracted increasing research interest in recent years [1,2]. The number of newly reported marine compounds increased steadily over the last decades up to almost 4000 new compounds described between 2001 and 2005 [2]. A wide variety of products from marine algae are of high actual or potential economic impact. Polyunsaturated fatty acids, carotenoids and phycocolloids are examples for marine products used in the food industry, while other compounds serve as templates for the development of new pharmaceutical drugs [3].

A remarkable group of marine natural products are the mycosporine-like amino acids (MAAs). An outstanding characteristic of these compounds is their high UV absorption with molar absorptivities (ɛ) of around 40 000 l mol⁻¹ cm⁻¹ (e.g. [4]). MAAs are water-soluble, low molecular-weight (generally <400) compounds composed of either an aminocyclohexenone or an aminocyclohexenimine ring, carrying nitrogen or amino alcohol substituents (see Fig. 1A) [5]. They are found in a wide variety of marine, freshwater and to a smaller degree in terrestrial organisms [6]. There is limited evidence that MAAs are derived from early steps of the shikimate pathway [7,8]. However, the biochemical pathway of MAA synthesis is still largely unknown, as well as its genetic base. The most primitive organisms capable of MAA synthesis are cyanobacteria (apart from one single bacterial species [9]). Among eukaryotic life, MAAs are synthesized in algae, fungi and lichens (symbioses between algae or cyanobacteria and fungi). Animals, which are lacking the shikimate pathway, but nevertheless contain MAAs in their body, are believed to derive these compounds either from their food or from symbiotic algae or cyanobacteria [10,11]. Recently this view has been challenged by the report of genes enconding enzymes of the shikimate pathway in the genome of a marine animal [12].

The function of MAAs in phototrophic organisms is primarily the protection of the organisms from deleterious UV radiation [13–15], but additionally they may function as compatible osmolytes [16] or as antioxidants [17]. Due to their high photostability MAAs are interesting candidates as UV sunscreens in cosmetic formulations [18,19]. Other UV absorbing compounds found in nature include scytonemins [20,21] and usnic acid [22]. The occurrence of these compounds is much more restricted than that of MAAs: Scytonemins are found only in cyanobacteria and cyanobacterial lichens [21,23] and usnic acid only in lichens [24]. Similar to MAAs, the synthesis of scytonemins and usnic acid is triggered by UV radiation and UV protection is an important function of these compounds [22,25]. In spite of these similarities, this review will focus on a comparison between MAAs and marine toxins.

Marine toxins have a tremendous economical impact due to their deleterious effects [26]. Poisonings by marine toxins can be grouped according to the chemical structures of the causative toxins and main symptoms of intoxication [26]: 1: Paralytic shellfish poisoning (PSP), caused by a group of closely related tetrahydropurine compounds including saxitoxin (STX), the first chemically characterized PSP toxin (see Fig. 1 B). 2: Diarrheic shellfish poisoning (DSP), caused by heat-stable polyether and lipophilic compounds isolated from various species of shellfish and dinoflagellates. 3: Domoic acid (see Figure 1 B) causing amnesic shellfish poisoning (ASP) sometimes also referred to as domoic acid poisoning. 4: Neurologic shellfish poisoning (NSP), caused by brevetoxins, tasteless, odourless, heat and acid stable, lipid soluble, cyclic polyether neurotoxins produced by the marine dinoflagellate Karenia brevis (formerly known as Gymnodinium breve or Ptychodiscus brevis [27]. 5: Azaspiracid shellfish poisoning, caused by azaspiracids. 6: Ciguatera fish poisoning (CFP), caused by ciguatera toxins, lipid soluble polyether compounds that are formed by biotransformation in the fish of precursor gambiertoxins. These poisonings in humans are caused by the ingestion of shellfish or fish that has accumulated toxins from their food. The primary producers of the aforementioned toxins are eukaryotic algae, mainly dinoflagellates. Only amnesic shellfish poisoning is caused by a diatom [28].

In freshwater environments, the main producers of toxins are prokaryotic cyanobacteria. The most frequently found cyanobacterial toxins in blooms from fresh and brackish waters are the cyclic peptide toxins of the microcystin (see Fig. 1 B) and nodularin families. Microcystins have been found in planktonic Anabaena, Microcystis, Oscillatoria (Planktothrix), Nostoc and Anabaenopsis species and in terrestrial members of the Hapalosiphon genus. Nodularin has been reported only from Nodularia spumigena [29]. Other cyanobacterial toxins are neurotoxins, including saxitoxin and analogues, anatoxin-a(S), an organophosphorous compound that acts as a potent irreversible acetyl cholinesterase inhibitor, and anatoxin-a [30].

To our knowledge there are no studies published addressing toxicity of MAAs. However, it seems likely that adverse effects, if there were any, would have been found empirically due to the widespread use of MAA-containing organisms as food, such as the red macroalga Porphyra sp. [31], terrestrial cyanobacteria of the genus Nostoc [32] and shellfish [33], without indications of adverse effects caused by MAAs. Nevertheless, the distribution of MAA synthesis and toxin production in a number of organisms leads to the question of possible relations between these groups of bioactive compounds.

Although there are more possible functions of MAAs in an organism, the role that is assumed primarily is the protection from deleterious UV radiation. Apart from antioxidant functions that have been reported exclusively for mycosporine-glycine [34,35] possible other roles of MAAs in desiccation tolerance as well as heat and cold tolerance are far less corroborated [36]. Merely circumstantial evidence for the UV-protective role of MAAs has been derived from the correlation of the MAA concentration and the UV radiation received by organisms. UV exclusion experiments showed that MAA concentrations in corals decline when grown under exclusion of UV radiation [37]. Numerous studies have shown correlations of MAA concentrations with gradients of UV radiation caused by water depth (e.g. [38]), UV transparency of water and altitude of the lakes (e.g. [39]) or latitudinal gradients [40]. Greater susceptibility to UV radiation was found in corals from deep water as compared to those from shallow water [38] and the photoinhibition of photosynthesis by UV radiation is decreased in dinoflagellates with high MAA concentrations induced by culture under high light conditions as compared to those with low MAA concentrations that were grown under low light. This protective effect was found, as could be expected, most pronounced in the wavelength range of maximal absorption by MAAs, i.e. between 310 and 360 nm [15]. The dinoflagellate Gyrodinium dorsum is able to tolerate at least twice as high doses of UV-B radiation before its motility is inhibited when it has been induced to synthesize MAAs by moderate UV-A radiation beforehand [13].

The UV-protective effect of MAAs is derived from their strong UV absorption with high molar absorptivities, their high photostability and the ability to dissipate the absorbed energy as heat. The photostability of MAAs is very high. The quantum yield of photodecomposition of the MAAs porphyra-334 and shinorine are 2.4 10⁻⁴ and 3.4 10⁻⁴, respectively [41]. In addition to the screening of cellular compounds from UV radiation, MAAs might also quench excited states of thymine by nonradiative energy transfer, and prevent the formation of photoproducts [42]. There is, however, no evidence for the importance of this mechanism in vivo.

Osmoprotective functions of MAAs might be concluded from their high abundance in organisms from hypersaline environments [16]. Highest MAA concentrations are generally found in organisms from marine or saline environments, but MAAs do not reach concentrations that could balance the osmolarity in the medium, so that additional compatible solutes, such as glycine-betaine or others, are required [36]. The possible involvement of MAAs in osmotic regulation was demonstrated in experiments in which the salinity of the medium was reduced by dilution with fresh water: the MAAs were rapidly excreted to the medium in amounts proportional to the degree of dilution [16].

An additional function of mycosporine-glycine may lie in the protection from oxidative stress. Whereas imino-MAAs having an cyclohexenimine core, like shinorine and porphyra-334, are not prone to oxidation, the oxo-MAA mycosporine-glycine that is constituted by an cyclohexenone core ring (see Fig. 1 A), shows a moderate antioxidant activity [17] and is an effective quencher of singlet oxygen generated by photosensitization [35]. The antioxidant activity has not only been demonstrated in vitro, but also in vivo: the coral Stylophora pistillata, containing only small amounts of mycosporine-glycine was found significantly more prone to heat-induced oxidative stress than Platygyra ryukyuensis containing a 20-fold higher concentration of mycosporine-glycine. Concomitant with the exposure to oxidative stress, a decline in the concentration of mycosporine-glycine was found in both species [34]. Singlet oxygen quenching activity in vitro has also been demonstrated for mycosporine-taurine but evidence for an antioxidative role in vivo is not available so far [43].

MAAs, although slightly different in their substituents, are a homogenous group of chemical compounds showing strong UV absorption. Marine toxins, in contrast are a structurally diverse group with the common denominator of toxicity. Some of the functions of marine toxins are connected with this characteristic, such as allelopathic effects [44] and the defence against herbivores [45]. It has been shown that microcystin-LR may exert a phytotoxic effect on aquatic macrophytes [46] resulting in growth inhibition, reduction in photosynthetic oxygen production and changes in pigment patterns. Detrimental effects of microcystin-RR on other freshwater phytoplankton species have been reported, with growth inhibition, chlorosis, changes in carbohydrate and protein content, among other symptoms [47]. However, no phytotoxic effects of microcystin-LR have been found in the aquatic macrophyte Lemna gibba [48].

An example of the strong effect of some toxins on grazers has been demonstrated, e.g., in experiments with the toxic dinoflagellate Prorocentrum lima, that produces okadaic acid and nauplii of the shrimp Artemia salina. Artemia cysts incubated in the cell-free culture medium of P. lima hatched, but mortalities were recorded for nauplii that hatched in, and metanuaplii exposed to, test solutions (autoclaved filtered seawater plus cell-free medium) that contained at least 50% of the cell-free medium. Animals exposed to cells of P. lima readily fed on the cells. Some nauplii, especially those just hatched, ingested only one cell before dying, while three days old nauplii ingested up to six cells before dying [45]. Even if the effect of toxins is not lethal to the grazer, toxic species may be avoided. In feeding experiments, the copepod Acartia tonsa was allowed to choose between toxic dinoflagellates (Alexandrium minutum), containing either low or high (up to 2.5 times more) amounts of PSP-toxins, and non-toxic alternative prey. The ingestion of the more toxic dinoflagellates was reduced while the ingestion of the non-toxic alternative remained unchanged [49].

The toxin domoic acid (DA) plays a role in the uptake of nutrients (Fe and Cu) and possibly the mitigation of Cu toxicity by acting as a chelating agent. The compound is released to the surrounding medium by toxin-producing diatoms under iron-limiting conditions. Fe acquisition improves markedly when DA is artificially added to the medium as well as the effect of Cu toxicity is reduced [50].

MAAs are reported from almost all algal taxonomic groups examined so far, however, highest concentrations are found in rhodophytes, dinoflagellates, cryptomonads and raphidophytes [51–53]. There are few studies addressing the presence of MAAs and toxins in aquatic organisms at the same time (e.g. [51]). Nevertheless, a general pattern of co-occurrence of MAAs and toxins in certain groups can be observed.

Marine toxins are transferred through the food chain from the algae producing them to animals feeding on them. Important sources of intoxication in humans are edible shellfish species. During the process of filtration the dinoflagellate cells and cysts are transported to the oesophagus and the stomach of the bivalve molluscs. The digestion takes place in the stomach and the diverticulae. The PSP toxins are released and enter the digestive organs. The particular toxin mixture retained in soft tissues of the shellfish varies in concentration and over time, and is determined by the species and strains of the dinoflagellates and shellfish as well as by other factors like environmental conditions [26]. But also other marine animals such as copepods are able to take up PSP toxins from their food and potentially transmit them to zooplankton-grazing fish, as suggested by high toxin concentrations in the latter [82].

MAAs are produced by algae and cyanobacteria, but they are also found in corals and other marine life forms including invertebrate and vertebrate animals (e.g. [83]). As the shikimic acid pathway is the supposed biosynthetic origin of MAAs, these compounds are presumably acquired either by the diet or by endosymbiotic algae [11]. The dietary acquisition and accumulation of MAAs from the diet was confirmed experimentally in the green sea urchin Strongylocentrotus droebachiensis maintained on a controlled diet of the marine red alga Mastocarpus stellatus, rich principally in the MAA shinorine [84]. MAAs were accumulated specifically in the ovaries of this organisms, while in other tissues no differences between the animals fed on a MAA-rich diet and the control animals were found. Embryos of this sea urchin from adults fed an MAA-rich diet showed a significant MAA concentration-dependent protection from UVR-induced cleavage delay compared with those from urchins fed a diet lacking MAAs [14]. Similar feeding experiments were conducted with marine crustaceans species, the amphipod Amphitoe valida and the isopod Idothea baltica, from the mid-littoral of the Patagonia coast (Argentina). These showed a species-specific accumulation behavior in the two organisms. Fed on a diet rich in MAAs, A. valida accumulated higher concentrations of MAAs as compared to I. baltica, and A. valida with high MAA concentrations was found more resistant to UV-B radiation than the same organism with low MAA concentrations [85]. The ability to acquire MAAs from food has also been tested in medaka fish (Oryzias latipes) and in mice, and it was found that the teleost fish was able to acquire MAAs from the diet and accumulate them specifically in the eye, while the mammal was not [86].

Although details of the biosynthesis of MAAs in marine algae and phototrophic symbioses remain to be demonstrated, it is commonly assumed that they are derived from early steps of the shikimate pathway. Favre-Bonvin et al. [7] suggested that the shikimate pathway intermediate, 3-dehydroquinate (DHQ), is the precursor for the six-membered carbon ring common to fungal mycosporines (Fig. 1). Synthesis of fungal mycosporines and of MAAs presumably proceeds from DHQ via gadusols (cyclohexenones) (Figure 2) [6]. Other natural compounds containing cyclohexenone rings are ketocarotenoids such as echinenone and canthaxanthin. Echinenone is produced from β-carotene by the introduction of a keto-group into the β-ionone ring (for a review see e.g. [87]). In the mycotoxin griseofulvin from Penicillium griseofulvum, radioactively labeled acetate is incorporated in the cyclohexenone ring structure [88]. In contrast to this neither in the ring structure of fungal mycosporines [7] nor in that of cyanobacterial MAAs [89] radioactively labelled acetate is incorporated. Thus it can be assumed that in spite of similar structural features MAA biosynthesis differs fundamenally from ketocarotenoid and griseofulvin biosynthesis.

As for MAAs, the biosynthetic pathways of many marine toxins are not fully understood. Microcystin biosynthesis has been first elucidated in two Microcystis strains [90–92]. The mcy gene cluster in Microcystis encodes six multienzymes that can be assigned to the family of nonribosomal peptide synthetases (NRPS) and type I polyketide synthases (PKS-I), respectively. Nonribosomal peptides (NRP) and polyketides are a structurally diverse group of secondary metabolites that have been identified in a number of prokaryotes and lower eukaryotes [93].

The structure of the cyanobacterial cyclic peptides are obviously much more complex than those of MAAs, but nevertheless, they share the use of amino acids (or amino alcohols, in the case of some MAAs) as building blocks. The multitude of mycosporines and MAAs is mainly due to different combinations of amino acids or amino alcohols attached at two positions of the central ring (for examples see Fig. 1 A). Thus the function of some (even as yet unknown) enzymes involved in MAA synthesis resembles that of NRPS - they incorporate an amino acid into a larger molecule.

MAAs and marine toxins show a broad overlap in the taxonomic distribution of their occurrence. They are mainly produced by cyanobacteria and algae, and MAAs as well as toxins are transmitted via food chains to organisms of higher trophic levels. In contrast to the transmission of toxins that causes severe adverse effects on animals, so far there is no evidence for any adverse effects of MAAs on any kind of organism. The biosynthetic pathways of many marine toxins and of MAAs are not fully elucidated but MAAs share the use of amino acids as building blocks with the cyclic peptide toxins of cyanobacteria. Further research on the genes involved in MAA synthesis will help to resolve the question of a possible relationship between NRPS and MAA synthesis.