Ultraviolet-protective compounds, such as mycosporine-like amino acids (MAAs) and related gadusols produced by some bacteria, fungi, algae, and marine invertebrates, are critical for the survival of reef-building corals and other marine organisms exposed to high-solar irradiance. These compounds have also been found in marine fish, where their accumulation is thought to be of dietary or symbiont origin. In this study, we report the unexpected discovery that fish can synthesize gadusol de novo and that the analogous pathways are also present in amphibians, reptiles, and birds. Furthermore, we demonstrate that engineered yeast containing the fish genes can produce and secrete gadusol. The discovery of the gadusol pathway in vertebrates provides a platform for understanding its role in these animals, and the possibility of engineering yeast to efficiently produce a natural sunscreen and antioxidant presents an avenue for its large-scale production for possible use in pharmaceuticals and cosmetics.DOI: http://dx.doi.org/10.7554/eLife.05919.001

Nature is a prolific producers of bioactive natural products with an array of biological activities and impact on human and animal health. But with great power comes great responsibility, and the organisms that produce a bioactive compound must be resistant to its biological effects to survive during production/accumulation. Microorganisms, particularly bacteria, have developed different strategies to prevent self-toxicity. Here, we review a few of the major mechanisms including the mechanism of resistance with a focus on self-resistant protein variants, target proteins that contain amino acid substitutions to reduce the binding of the bioactive natural product, and therefore its inhibitory effects are highlighted in depth. We also try to identify some future avenues of research and challenges that need to be addressed.

Background:The emergence of drug-resistant tuberculosis has called for the discovery of new antitubercular drugs. Results: We successfully generated 24-desmethylrifampicin by modifying the rifamycin polyketide backbone. Conclusion: 24-Desmethylrifamycin showed better antibacterial activity than rifampicin against multidrug-resistant strains of Mycobacterium tuberculosis. Significance: The combined genetic-synthetic strategy used in the study has opened up new avenues for generating more rifamycin analogs.

2-epi-5-epi-Valiolone synthase (EEVS), a C7-sugar phosphate cyclase (SPC) homologous to 3-dehydroquinate synthase (DHQS), was discovered during studies of the biosynthesis of the C7N-aminocyclitol family of natural products. EEVS was originally thought to be present only in certain actinomycetes, but analyses of genome sequences showed that it is broadly distributed in both prokaryotes and eukaryotes, including vertebrates. Another SPC, desmethyl-4-deoxygadusol synthase (DDGS), was later discovered as involved in the biosynthesis of mycosporine-like amino acid sunscreen compounds. Current database annotations are quite unreliable, with many EEVSs reported as DHQS, and most DDGSs reported as EEVS, DHQS, or simply hypothetical proteins. Here, we identify sequence features useful for distinguishing these enzymes, report a crystal structure of a representative DDGS showing the high similarity of the EEVS and DDGS enzymes, identify notable active site differences, and demonstrate the importance of two of these active site residues for catalysis by point mutations. Further, we functionally characterized two representatives of a distinct clade equidistant from known EEVS and known DDGS groups, and show them to be authentic EEVSs. Moreover, we document and discuss the distribution of genes that encode EEVS and DDGS in various prokaryotes and eukaryotes, including pathogenic bacteria, plant symbionts, nitrogen-fixing bacteria, myxobacteria, cyanobacteria, fungi, stramenopiles, and animals, suggesting their broad potential biological roles in nature.

Glycosyltransferases are ubiquitous in nature. They catalyze a glycosidic bond formation between sugar donors and sugar or non-sugar acceptors to produce oligo/polysaccharides, glycoproteins, glycolipids, glycosylated natural products, and other sugar-containing entities. However, a trehalose 6-phosphate synthase-like protein has been found to catalyze an unprecedented non-glycosidic C-N bond formation in the biosynthesis of the aminocyclitol antibiotic validamycin A. This dedicated ‘pseudoglycosyltransferase’ catalyzes a condensation between GDP-valienol and validamine 7-phosphate to give validoxylamine A 7′-phosphate with net retention of the ‘anomeric’ configuration of the donor cyclitol in the product. The enzyme operates in sequence with a phosphatase, which dephosphorylates validoxylamine A 7′-phosphate to validoxylamine A.