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Eric W. Schmidt

Professor of Medicinal Chemistry and
Adjunct Professor of Biology

Eric Schmidt Photo

B.S. University of California, San Diego

Ph.D. University of California, San Diego

Research

References

ews1@utah.edu

Eric Schmidt's Lab Page

Eric Schmidt's PubMed Literature Search

Molecular Biology Program

Biological Chemistry Program

Symbiosis, microbiome, metagenomics, synthetic biology, natural products chemistry, biosynthesis

Research

Secondary metabolites (natural products) are central both to interactions between organisms and to human health.  For example, in the oceans secondary metabolites protect otherwise defenseless animals from predation, and the same defensive molecules have been applied to develop anticancer agents.  The goals of my lab are (i) to understand the basic biology and chemistry of secondary metabolism; (ii) to apply that understanding to synthetic biology and metabolite engineering; (iii) to understand the chemical mechanisms of biosynthetic enzymes; and (iv) to discover and develop new drug lead natural products. 

To address these interdisciplinary questions, my lab employs many different experimental methods, including: spectroscopy; enzyme expression, purification, and biochemical analysis; organic and analytical chemistry; genome and metagenome sequencing and analysis; medicinal chemistry; bacterial and fungal genetics; bioactivity testing; bacterial culture; and natural products chemistry. We also have forged numerous collaborations to further broaden the scope of projects.

Research area 1. Symbiosis and natural products.

Marine animals are renowned sources of natural products with pharmaceutical potential. Research shows that several compounds are not made by the animals themselves, but rather by symbiotic bacteria. My lab is working to achieve a fundamental understanding of the players involved in synthesizing secondary metabolites in marine animals. We apply this knowledge in the discovery and engineering of small molecules with therapeutic potential.

Research area 2. RiPP biosynthesis.

The ribosomally synthesized natural products (RiPPs) are among the most ubiquitous and abundant bioactive compounds in nature. We study how they are synthesized from a biochemical and synthetic biology perspective.

Research area 3. Neuroactive molecules from mollusk-symbiotic bacteria.

Cultivated bacteria are rich sources for discovery of new bioactive agents. In a collaborative project with researchers in the Philippines and the US, we are exploring the potential of mollusk symbionts to synthesize natural products that affect neurons and that have potential to treat disease.

Schmidt Figure OneSchmidt Figure TwoSchmidt Figure ThreeSchmidt Figure Four

References

  1. Lin, Z.; Smith, M.D.; Concepcion, G.P.; Haygood, M.G.; Olivera, B.M.; Light, A.; Schmidt, E.W. Modulating the serotonin receptor spectrum of pulicatin natural products. J. Nat. Prod. 2017. epub.

  2. Aihara, K.; Inokuma, T.; Jichu, T.; Lin, Z.; Fu, F.; Yamaoka, K.; Shigenaga, A.; Hutchins, D.A.; Schmidt, E.W.; Otaka, A. Cysteine-free intramolecular ligation of N-sulfanylethylanilide peptide using 4-mercaptobenzylphosphonic acid: Synthesis of cyclic peptide, trichamide. Syn. Lett2017, epub.

  3. Olivera, B.M.; Raghuraman, S.; Schmidt, E.W.; Safavi-Hemami, H. Linking neuroethology to the chemical biology of natural products: Interactions between cone snails and their fish prey, a case study. J. Comp. Physiol. A 2017, epub.

  4. Distel, D.L.;* Altamia, M.A.; Lin, Z.; Shipway, J.R.; Han, A.; Forteza, I.; Antemano, R.; Limbaco, G.; Tebo, A.; Dechavez, R.; Albano, J.; Concepcion, G.; Schmidt, E.W., Haygood, M.G.* Wooden steps to chemoautotrophy for a giant bivalve. Proc. Natl. Acad. Sci. U S A 2017, epub. *co-corresponding.

  5. Sardar, D.; Hao, Y.; Lin, Z.; Morita, M.; Nair, S.K.;* Schmidt, E.W.* Enzymatic N- and C-protection in cyanobactin RiPP natural products. J. Am. Chem. Soc2017, epub. *co-corresponding.

  6. Zhang, S.; Qiu, Y.; Kakule, T.; Lu, Z.; Xu, F.; Lamb, J.G.; Reilly, C.; Zheng, Y.; Sham, S.W.; Wang, W.; Xuan, L.-J.; Schmidt, E.W.; Zhan, J. Identification of cyclic depsipeptides and their dedicated synthetase fromHapsidospora irregularis. J. Nat. Prod2017, epub.

  7. Agarwal, V.; Blanton, J.M.; Podell, S.; Taton, A.; Schorn, M.A.; Busch, J.; Lin, Z.; Schmidt, E.W.; Jensen, P.R.; Paul, V.J.; Biggs, J.S.; Golden, J.W.; Allen, E.E.; Moore, B.S. Metagenomic discovery of polybrominated diphenyl ether biosynthesis in marine sponge microbiomes. Nat. Chem. Biol. 2017, epub.

  8. Hao, Y.; Pierce, E.; Roe, D.R.; Morita, M.; McIntosh, J.A.; Agarwal, V.; Cheatham, T.E.; Schmidt, E.W.,* Nair, S.K.* Molecular basis of broad-substrate selectivity of a peptide prenyltransferase. Proc. Natl. Acad. Sci. U S A 2016, epub. *co-corresponding

  9. Sardar, D.; Tianero, M.D.; Schmidt, E.W. Directing biosynthesis: practical supply of natural and unnatural cyanobactins. Methods Enzymol. 2016 epub.

  10. Lin, Z.; Schmidt, E.W. Origin of chemical diversity in the Prochloron-tunicate symbiosis. Appl. Environ. Microbiol201682, 3450-3460.

  11. Tianero, M.D.; Pierce, E.; Sardar, D.; Raghuraman, S.; McIntosh, J.A.; Heemstra, J.R.; Schonrock, Z.; Covington, B.C.; Cox, J.E.; Bachmann, B.O.; Olivera, B.M.; Ruffner, D.E.; Schmidt, E.W. Metabolic model for diversity-generating metabolism. Proc. Natl. Acad. Sci. U S A 2016113, 1772-1777.

  12. Sardar, D.; Schmidt, E.W. Combinatorial biosynthesis of RiPPs: Docking with marine life. Curr. Op. Chem. Biol. 201613, 15-21.

  13. Neves, J.L.; Lin, Z.; Imperial, J.S.; Vasconcelos, V.; Olivera, B.M.;* Schmidt, E.W.* Small molecules in the cone snail arsenal. Org. Lett. 201517, 4933-4935. * co-corresponding

  14. Schmidt, E.W. Natural products: Hunting microbial metabolites. Nat. Chem. 20157, 375-376.

  15. Kakule, T.B.; Zhang, S.; Zhan, J.; Schmidt, E.W. Biosynthesis of the tetramic acids Sch210971 and Sch210972. Org. Lett.  201517, 2295-2297.

  16. Sardar, D.; Lin, Z.; Schmidt, E.W. Modularity of RiPP enzymes enables designed synthesis of decorated peptides. Chem. Biol. 201522, 907-916.

  17. Ruffner, D.E.; Schmidt, E.W.; Heemstra, J.R. Assessing the combinatorial potential of the RiPP cyanobactintru pathway. ACS Synth. Biol. 20154, 482-492.

  18. Teichert, R.W.; Schmidt, E.W.; Olivera, B.M. Constellation Pharmacology: A new paradigm for drug discovery. Ann. Rev. Pharm. Tox. 201555, 573-589.

  19. Schmidt, E.W. The secret to a successful relationship: Lasting chemistry between ascidians and their symbiotic bacteria. Invert. Biol. 2015134, 88-102.

  20. Tianero, M.D.; Kwan, J.C.; Wyche, T.; Koch, M.; Barrows, L.R.; Bugni, T.S.; Schmidt, E.W. Species specificity of symbiosis and secondary metabolism in ascidians. ISME J. 20159, 615-628.

  21. Sardar, D.; Pierce, E.; McIntosh, J.A.; Schmidt, E.W. Recognition sequences and substrate evolution in cyanobactin biosynthesis. ACS Synth. Biol20154, 167-176.

  22. Schmidt, E.W. Biosynthetic approaches to marine drug discovery and development. In: Marine Drugs, Baker, B editor. 2015 invited chapter.

  23. Schmidt, E.W. The secret to a successful relationship: lasting chemistry between ascidians and their symbiotic bacteria. Invertebr Biol.2015, 134, 88-102.
  24. Schmidt, E.W. Natural products: Hunting microbial metabolites. Nat Chem.2015, 7, 375-6.
  25. Kakule, T.B.; Zhang, S.; Zhan, J.; Schmidt, E.W. Biosynthesis of the tetramic acids sch210971 and sch210972. Org Lett.2015, 17, 2295-7.
  26. Teichert, R.W.; Schmidt, E.W.; Olivera, B.M. Constellation pharmacology: a new paradigm for drug discovery. Annu Rev Pharmacol Toxicol.2015, 55, 573-89.
  27. Kakule, T.B.; Lin, Z.; Schmidt, E.W. Combinatorialization of fungal polyketide synthase-peptide synthetase hybrid proteins. J Am Chem Soc.2014, 136, 17882-90.
  28. Jadulco, R.C.; Koch, M.; Kakule, T.B.; Schmidt, E.W.; Orendt, A.; He, H., Janso, J.E.; Carter, G.T.; Larson, E.C.; Pond, C.; Matainaho, T.K.; Barrows, L.R. Isolation of pyrrolocins A-C: cis- and trans-decalin tetramic acid antibiotics from an endophytic fungal-derived pathway. J Nat Prod. 2014, 77, 2537-44.
  29. Kakule, T.B.; Jadulco, R.C.; Koch, M.; Janso, J.E.; Barrows, L.R.; Schmidt, E.W. Native promoter strategy for high-yielding synthesis and engineering of fungal secondary metabolites. ACS Synth Biol.2015, 4, 625-33.
  30. Lin, Z.; Koch, M.; Abdel Aziz, M.H.; Galindo-Murillo, R.; Tianero, M.D.; Cheatham T.E.; Barrows, L.R.; Reilly, C.A.; Schmidt, E.W. Oxazinin a, a pseudodimeric natural product of mixed biosynthetic origin from a filamentous fungus. Org Lett.2014, 16, 4774-7.
  31. Tianero, M.D.; Kwan, J.C.; Wyche, T.; Koch, M.; Barrows, L.R.; Bugni, T.S.; Schmidt, E.W. Species specificity of symbiosis and secondary metabolism in ascidians. ISME J.2015,9, 615-28.
  32. Lin, Z.; Zachariah, M.M.; Marett, L.; Hughen, R.W.; Teichert, R.W.; Concepction, G.P.; Haygood, M.G.; Olivera, B.M.; Light, A.R.; Schmidt, E.W. Griseorhodins D-F, neuroactive intermediates and end products of post-PKS tailoring modification in griseorhodin biosynthesis. J. Nat. Prod.2014, 77, 1224-30.
  33. Sardar, D.; Pierce, E.; McIntosh, J.A.; Schmidt, E.W. Recognition sequences and substrate evolution in cyanobactin biosynthesis. ACS Synth. Biol. 2014,4, 167-76.
  34. Kwan, J.C.; Tianero, M.D.; Donia, M.S.;Wyche, T.P.; Bugni, T.S.; Schmidt, E.W. Host control of symbiont natural product chemistry in cryptic populations of the tunicate Lissoclinum patella.PLoS One2014, 9, e95890.
  35. Lin, Z.; Koch, M.; Pond, C.D.; Mabeza, G.; Seronay, R.A.; Concepcion, G.P.; Barrows, L.R.; Olivera, B.M.; Schmidt, E.W. Structure and activity of lobophorins from a turrid mollusk-associated Streptomyces sp. J. Antibiot.2014, 67, 121-126.
  36. Kwan, J.C.; Schmidt, E.W. Bacterial endosymbiosis in a chordate host: Long-term co-evolution and conservation of secondary metabolism. PLoS One2013, 8, e80822.
  37. Lin, Z.; Marett, L.; Hughen, R.W.; Flores, M.; Forteza, M.; Ammon, M.A.; Concepcion, G.P.; Espino, S.; Olivera, B.M.; Rosenberg, G.; Haygood, M.G.; Light, A.R.; Schmidt, E.W. Neuroactive diol and acyloin metabolites from cone snail-associated bacteria. Bioorg. Med. Chem. Lett.2013, 23, 4867-4869.
  38. Kakule, T.; Sardar, D.; Lin, Z.; Schmidt, E.W. Two related pyrrolidinedione synthetase loci in Fusarium heterosporum ATCC 74349 produce divergent metabolites. ACS Chem. Biol.2013, 8, 1549-1557.
  39. McIntosh, J.A.; Lin, Z.; Tianero, M.D.; Schmidt, E.W. Aestuaramides, natural cyanobactin cyclic peptides resulting from isoprene-derived Claisen rearrangements. ACS Chem. Biol. 2013, 8, 877-883.
  40. Elshahawi, S.I.; Trinidade-Silva, A.E.; Hanora, A.; Han, A.W.; Flores, M.; Vizzoni, V.; Schrago, C.G.; Concepcion, G.P.; Distel, D.L.; Soares, C.A.; Schmidt, E.W.; Haygood, M.G. A boronated tartrolon antibiotic produced by symbiotic cellulose-degrading bacteria in shipworm gills. Proc. Natl. Acad. Sci. U S A 2013, E295-304.
  41. Lin, Z.; Torres, J.; Ammon, M.A.; Marett, L.; Teichert, R.W.; Reilly, C.A.; Kwan, J.C.; Hughen, R.W.; Flores, M.; Peraud, O.; Light, A.; Villaraza, A.; Haygood, M.G.; Concepcion, G.P.; Olivera, B.M.; Schmidt, E.W. A bacterial source for mollusk pyrone polyketides. Chem. Biol. 2013, 20, 73-81.
  42. Kwan, J.C.; Donia, M.S.; Han, A.; Hirose, E.; Haygood, M.G.; Schmidt, E.W. Genome streamlining for chemical defense in a coral reef symbiosis. Proc. Natl. Acad. Sci. U S A2012, 109, 20655-20660.
  43. Hou, Y.; Tianero, D.; Kwan, J.C.; Wyche, T.P.; Cole, M.R.; Ellis, G.A.; Vazquez-Rivera, E.; Braun, D.R.; Rose, W.E.; Schmidt, E.W.; Bugni, T.S. Structure and biosynthesis of the antibiotic bottromycin D. Org. Lett.2012, 14, 5050-5053.
  44. Agarwal, V.; Pierce, E.; McIntosh, J.; Schmidt, E.W.; Nair, S.K. Structures of cyanobactin maturation enzymes define a new family of transamidating proteases. Chem. Biol.2012, 19, 1411-1422.
  45. Lin, Z.; Falkinham, J.O.; Tawfik, K.; Jeffs, P.; Cox, J.E.; Schmidt, E.W. Burkholdines from Burkholderia ambifaria: Antifungal agents and possible virulence factors. J. Nat. Prod.2012, 75, 1518-1523.
  46. Lin, Z.; Flores, M.; Forteza, I.; Concepcion, G.P.; Rosenberg, G.; Haygood, M.G.; Olivera, B.M.; Light, A.; Schmidt, E.W. Totopotensamides, polyketide-cyclic peptide hybrids from a mollusk-associated bacterium Streptomyces sp. J. Nat. Prod.2012, 75, 644-649.

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Last Updated: 8/4/17