Eric W. Schmidt
Associate Professor of Medicinal Chemistry
B.S. University of California, San Diego
Ph.D. University of California, San Diego
Eric Schmidt's Lab Page
Eric Schmidt's PubMed Literature Search
Research
A majority of the world’s most potent and lifesaving pharmaceuticals are derived in one way or another from natural products. These small molecules are produced by a diversity of organisms, especially bacteria, fungi, and plants. Two amazing features of natural products are their efficacy in hitting disease-relevant targets and their structural diversity. It makes sense that natural products should very effectively target specific biological macromolecules. They have a long history of evolving in concert with their biological targets and are finely tuned for communication between organisms. The enormous structural diversity encompassed by natural products is less easy to explain. Hundreds of thousands of small molecules have been cataloged containing functional groups that are bizarre and architectures that are unusual. It remains an open question as to what the underlying genetic mechanisms are that lead to this chemical diversity.
These mechanisms are more than just a curiosity. Recent years have seen the increasing application of the tools of genetic engineering to natural products. Instead of synthesizing natural products and their analogs in the lab, it is increasingly possible to produce them by rational manipulation of the underlying genes — organic synthesis using genetic engineering. However, this engineering remains quite challenging for many reasons. By observing natural pathways to chemical evolution, it is possible to replicate them in the lab, greatly speeding the process.
Much of the interaction between organisms is mediated by natural products. For example, organisms can defend themselves against predation by synthesizing toxins, or they can attack using natural products. More subtle interactions involving gentler methods of communication are also widespread. In most cases, these natural products are not “general toxins”, but instead very selectively target certain types of macromolecules. As such, they may be very rapidly evolving in concert with their targets or to hit new targets.
In my laboratory, we apply the tools of organic synthesis, natural products chemistry, genetic engineering, and biochemistry to understand the origin and evolution of natural products. We are particularly interested in symbiotic interactions, where bacteria or fungi are living in close contact with animal hosts. Tropical reefs are incredibly rich in such associations, and tropical reef animals often contain small molecules that are drug leads for human diseases. We are using these associations in metagenomic (environmental genomic) approaches to understand pathway evolution and diversity. Along the way, we have discovered new small molecules, new genes, and new groups of enzymes. We are using these results to engineer production of small molecule libraries for the treatment of human diseases.
References
1. *Lee JH, *McIntosh J, *Hathaway BJ, Schmidt EW (2009) Using marine natural products to discover a protease that catalyzes peptide macrocyclization of diverse substrates. J. Am. Chem. Soc. 131:2122-2124
2. *McIntosh J, *Donia MS, Schmidt EW (2009) Ribosomal peptide natural products: bridging the ribosomal and nonribosomal worlds. Nat. Prod. Rep. 26:537-559
3. Schmidt EW, *Donia MS (2009) Cyanobactin ribosomal peptides — a case of deep metagenome mining. Methods Enzymol. 458:575-596
4. Schmidt EW (2008) Trading molecules and tracking targets in symbiotic interactions. Nature Chem. Biol. 4:466-473
5. *Sims JW, Schmidt EW (2008) Thioesterase-like role for fungal PKS-NRPS hybrid reductive domain. J. Am. Chem. Soc. 130:11149-11155
6. *Donia MS, Ravel J, Schmidt EW (2008) A global assembly line for cyanobactins. Nature Chem. Biol. 4:341-3
* indicates Schmidt lab graduate student
3. Donia M, Hathaway BJ, Sudek S, Haygood MG, Rosovitz MJ, Ravel J, Schmidt EW (2006) Natural combinatorial peptide libraries in cyanobacterial symbionts of marine ascidians. N at. Chem. Biol. 2:729-735
4. Sudek S, Haygood MG, Youssef DTA, Schmidt EW (2006) Structure of trichamide, a cyclic peptide from the bloom-forming bacterium Trichodesmium erythraeum, predicted from the genome sequence. Appl. Environ. Microbiol. 72:4382-4387
5. Schmidt EW, Nelson JT, Rasko DA, Sudek S, Eisen J, Haygood MG, Ravel J (2005) Patellamide A and C biosynthesis by a microcin-like pathway in Prochloron didemni , the cyanobacterial symbiont of Lissoclinum patella . Proc. Natl. Acad. Sci. USA 102:7315-20
6. Schmidt EW (2005) From chemical structure to environmental biosynthetic pathways: navigating marine invertebrate-bacteria associations. Trends Biotechnol., accepted
7. Sims JW, Fillmore JP, Warner DD, Schmidt EW (2005) Equisetin biosynthesis in Fusarium heterosporum . Chem. Commun. 186-188
8. Schmidt EW, Sudek S, Haygood MG (2004) Genetic evidence supports secondary metabolic diversity in Prochloron spp., the cyanobacterial symbiont of a tropical ascidian. J. Nat. Prod. 67:1341-1345
9. Schmidt EW, Nelson JT, Fillmore JP (2004) Synthesis of tyrosine derivatives for saframycin MX1 biosynthetic studies. Tetrahedron Lett. 45:3921-3924
10. Schmidt EW, Raventos-Suarez C, Bifano M, Menendez AT, Fairchild C, Faulkner DJ (2004) Scleritodermin A, a cytotoxic peptide from the lithistid sponge, Scleritoderma nodosum . J. Nat. Prod. 67:475-478
11. Hitchman TS, Schmidt EW, Rarick MA, Linz JE, Townsend CA (2001) Hexanoate synthase, a specialized type I fatty acid synthase in aflatoxin B 1 biosynthesis. Bioorganic Chem. 29:293-307
12. Schmidt EW, Obraztsova AY, Davidson SK, Faulkner DJ, Haygood MG (2000) The peptide containing symbiont of the marine sponge Theonella swinhoei is a novel d -proteobacterium, " Candidatus Entotheonella palauensis." Mar. Biol. 136:969-977
13. Schmidt EW, Bewley CA, Faulkner DJ (1998) Theopalauamide, a bicyclic glycopeptide from filamentous bacterial symbionts of the lithistid sponge Theonella swinhoei from Palau and Mozambique. J. Org. Chem. 63:1254-1258
