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An Enzymatic Route to Sunscreens

Organisms use chemical strategies to prevent and mitigate damage from solar irradiation. 2] A particularly common form of UV protection involves mycosporines and their relatives, the mycosporine amino acids (MAAs). For example, many types of shallow-water marine invertebrates and cyanobacteria contain mycosporine derivatives, as do many fungi and basal eukaryotes. MAAs have also been commercialized as sunscreen products for human use. Despite the MAAs wide occurrence and their commercial and environmental importance, very little was known about their genetic and biochemical origin. A recent series of advances has solved key problems and culminated in a report by Balskus and Walsh characterizing the pathway to the MAA shinorine. These new results reveal that the proposed MAA biosynthetic pathway is incorrect. The pathway exhibits very unusual mechanistic twists on rather common types of enzymes. The biochemical and genetic data explain the biosynthesis and distribution of this important metabolite class. Based upon structural considerations, MAAs were thought to arise from the canonical shikimate-pathway intermediate, 3dehydroquinic acid (DHQ), which would then be further modified by methylation, reduction, and conjugation to amino acids and sometimes sugars (Scheme 1). Similarly, there are many secondary metabolites—such as a subset of aminoglycosides—that contain cyclohexyl core structures resembling shikimate-pathway products. In the core shikimate pathway, which leads to aromatic amino acids and many secondary metabolites, 3-deoxy-d-arabinoheptulosonate 7-phosphate is converted by the action of dehydroquinate synthase (DHQS) into DHQ. DHQ could then potentially serve as an intermediate to the diverse shikimate-like products, including MAAs. Indeed, in the case of MAAs, indirect evidence implicated the canonical DHQ as the major pathway intermediate. Complicating this picture, homologous DHQS-like pathways have been discovered that have other substrates and products. MAAs are commonly isolated from shallow-water cnidarians, such as sea anemones, that are exposed to high UV irradiation, yet animals in general are not thought to make shikimic acid metabolites. 2] Because dinoflagellates live in symbiotic association with many cnidarians, it was possible that they were the ultimate source of MAAs in animals, but contradictory evidence existed in some species. Starcevic et al. took a bioinformatics approach, using the genome for the anemone, Nematostella vectensis. A DHQS homologue was discovered in the animal genome, and convincing phylogenetic evidence pointed to lateral gene transfer from bacteria as the ultimate source of the genes. The authors noted that the DHQS homologue was most similar to a gene from the chloroplast of dinoflagellates that was fused to a putative O-methyltransferase (OMT) gene. The OMT was also present in N. vectensis, but not as a fusion protein. The authors speculated that these genes could be involved in MAA synthesis, through the intermediacy of DHQ. The presence of an OMT could indicate that this pathway led to MAAs, since the putative DHQ intermediate requires methylation in all known mycosporine derivatives. It has become increasingly clear that DHQS-family proteins are not limited to the canonical DHQ reaction. In fact, bacteria use an array of DHQS-like enzymes with different substrates and products, so that DHQ itself is not a common intermediate. Prior to the anemone manuscript, Wu et al. reported a phylogenetic analysis of bacterial and fungal DHQS-like enzymes that led to the discovery that the enzymes group according to their substrates and products. Although many of the DHQS proteins clustered into distinct families representing known compounds, the authors also identified a mystery family from cyanobacteria and fungi, for which no products were known. A major advance from this manuscript was the delineation of active-site-lining residues that were important for selectivity. In the mystery DHQS family, it was clear that the binding pocket differed from those for other families; this indicated potentially new substrates and/or products. Because the DHQS family was very similar to that from N. vectensis, this Scheme 1. DHQS-like enzymes lead to the synthesis of many different products, including DHQ, the predicted precursor of MAAs such as shinorine. However, a recent study shows that 4-deoxygadusol is synthesized directly by a DHQS-like enzyme.