Many drugs and drug candidates isolated from invertebrates are actually produced by unknown symbiotic microorganisms. Often these microbes cannot be cultured, making it difficult to identify the enzymes that generate the secondary metabolites of interest. Two recent studies use metagenomics—the sequencing of entire microbial communities—to elucidate the biology underlying the synthesis of natural products in symbionts. The anti-cancer compound ecteinascidin-743 (ET-743) derives from the tunicate Ecteinascidia turbinata. Purifying ET-743 directly from tunicates is impractical because of the low yields, and newer semisynthetic methods are costly. Rath et al. sequenced the total DNA of the Ecteinascidia turbinata microbial consortium and identified both the source microbe and 25 core biosynthetic genes. In a related project, Donia et al. worked with four samples of the symbiotic microbiome from the tunicate host Lissoclinum patella. Sequencing revealed a wealth of information on the chemical exchanges that support symbiosis and on metabolites that have potential as drugs and fuels. The genomes assembled for one member of the microbiome, the cyanobacterium Prochloron didemni, are “the most complex so far assembled from uncultivated organisms.” (ACS Chem. Biol. 6, 1244–1256, 2011; Proc. Natl. Acad. Sci. USA. published online, doi: 10.1073/pnas.1111712108, 28 November 2011)
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