B.S. 2004, Chemistry and Molecular Genetics, State University of New York College at Fredonia
Ph. D. 2010, Scripps Institution of Oceanography, University of California at San Diego. NIH Predoctoral Fellow. Mentor: Bradley Moore
2010-2011, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Germany Mentor: Christian Hertweck
2011-2014, Department of Chemical and Biomolecular Engineering, University of California at Los Angeles. L’Oréal USA Postdoctoral Fellow. Mentor: Yi Tang
Secondary metabolites are specialized small molecules produced in nature and often possess a variety of biological activities that can be used toward improving our quality of life. These molecules possess exquisite chemical diversity and are often an inspiration for the development of new pharmaceutical agents. Research in the Winter lab is focused on 1) Elucidating the biosynthetic blueprint that nature uses for assembling secondary metabolites in bacteria and fungi, 2) Manipulating and reprograming biosynthetic systems for the generation of new compounds with enhanced bioactivity, and 3) Exploring the functional roles these molecules serve the producing organism, as well as their impact on the environment. To address these topics, we apply a multifaceted approach in our studies and implement research techniques from molecular genetics, biochemistry, chemistry, bioinformatics, structural biology and bioengineering.
Discovery and development of anti-microbial and anti-cancer agents
As secondary metabolites continue to be an inspiration for drug discovery programs, new chemical entities and molecules possessing novel modes of action are in high demand. Biological pressures can influence the chemical diversity of secondary metabolites and it has been shown that marine-derived microorganisms often produce molecules not observed in their terrestrial counterparts. These microorganisms serve as an ideal resource for drug discovery efforts and for the characterization of novel biosynthetic enzymes. We are specifically interested in marine-derived fungi that produce molecules with anti-microbial and anti-cancer properties. By identifying the corresponding biosynthetic clusters, we can 1) Interrogate the strategies that nature uses for synthesizing and installing unique functional groups responsible for the observed biological activity and 2) Use this information to incorporate new chemical features into existing molecular scaffolds and enhance their inherent biological activities.
In their host organisms, secondary metabolites are assembled and modified by specialized machinery. Often times, the complex structures or chemical modifications instated by these molecular assembly lines are difficult to replicate using traditional synthetic methods, which pose significant challenges when developing pharmaceutical agents or derivatives for testing in biological assays. We aim to develop alternative approaches for producing these otherwise inaccessible molecules or derivatives by 1) Reprogramming the biosynthetic machinery for the production of therapeutic agents with increased biological activities and 2) Develop the individual enzymes that carry out complicated reactions into renewable and environmentally friendly biocatalysts for the chemoenzymatic synthesis or derivatization of new chemical entities.
In addition to studying biologically active molecules, we are also interested in identifying virulence factors in fungi. Many fungi produce mycotoxins which are hazardous to human and animal health and can have devastating effects on food supplies. We are interested in 1) identifying and characterizing mycotoxin-producing clusters from fungal plant pathogens and 2) using this information for the development of antifungal and mycotoxin-detoxifying agents.
14. Sato, M.; Winter, J. M.; Noguchi, H.; Tang, Y.; Watanabe, K. (2016) Combinatorial Generation of Chemical Diversity by Redox Enzymes in Chaetoviridin Biosynthesis. Org. Lett. Accepted.
13. Cochrane, R. V. K.; Gao, Z.; Lambkin, G. R.; Xu, W.; Winter, J. M.; Marcus, S. L.; Tang, Y.; Vederas, J. C. (2015) Comparison of 10, 11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs. ChemBioChem. 16:2479-2483.
12. Winter, J. M.; Cascio, D.; Dietrich, D.; Sato, M.; Watanabe, K.; Sawaya, M. R.; Vederas, J. C.; Tang, Y. (2015) Biochemical and Structural Basis for Controlling Chemical Modularity in Fungal Polyketide Biosynthesis. J. Am. Chem. Soc. 137:9885-9893.
11. Winter, J. M. and Tang, Y. (2014) Getting a Handle on Peptides. Nat. Chem. 6:1037–1038.
10. Winter, J. M.; Chiou, G.; Bothwell, I.; Xu, W.; Garg, N. K.; Luo, M. K.; Tang, Y. (2013) Expanding the Structural Diversity of Polyketides by Exploring the Cofactor Tolerance of an Inline Methyltransferase Domain. Org. Lett. 15, 3774-3777.
9. Winter, J.M.; Sato, M.; Sugimoto, S.; Chiou, G.; Garg, N. K.; Tang, Y.; Watanabe, K. (2012) Identification and Characterization of the Chaetoviridin and Chaetomugilin Gene Cluster in Chaetomium globosum Reveal Dual Functions of an Iterative Highly-Reducing Polyketide Synthase. J. Am. Chem. Soc. 134, 17900–17903.
8. Winter, J. M. and Tang, Y. (2012) Synthetic Biological Approaches to Natural Product Biosynthesis. Curr. Opin. Biotechnol. 23:736–743.
7. Winter J. M.; Behnken S.; Hertweck C. (2011) Genomics-Inspired Discovery of Natural Products. Curr. Opin. Chem. Biol. 15:22–31.
6. Bernhardt, P.; Okino, T.; Winter, J. M.; Miyanaga, A.; Moore, B. S. (2011) A Stereoselective Vanadium-Dependent Chloroperoxidase in Bacterial Antibiotic Biosynthesis. J. Am. Chem. Soc. 133:4268–4270.
5. Udwary, D. W.; Gontang, E. A.; Jones, A. C.; Schultz, A. W.; Sorrels, C. M.; Winter, J. M.; Yang, J. Y.; Beauchemin, N.; Capson, T. L.; Clark, B. R.; Esquenazi, E.; Eustaquio, A. S.; Freel, K.; Gonzalez, D.J.; Gerwick, L.; Gerwick, W. H.; Liu, W.; Malloy, K. L.; Maloney, K. N.; Nett, M.; Nunnery, J. K.; Penn, K.; Prieto-Davo, A.; Simmons, T. L.; Weitz, S.; Wilson, M. C.; Tisa, L. S.; Dorrestein P. C.; Moore, B. S. (2011) Significant Natural Product Biosynthetic Potential of Actinorhizal Symbionts of the Genus Frankia, as Revealed by Comparative Genomic and Proteomic Analyses. Appl. Environ. Microbiol. 77:3617–3625.
4. Winter, J. M. and Moore, B. S. (2009) Exploring the Chemistry and Biology of Vanadium-Dependent Haloperoxidases. J. Biol. Chem. 284:18577–18581.
3. Winter, J. M.; Jansma, A. L.; Handel, T. M.; Moore, B. S. (2009) Formation of the Pyridazine Natural Product Azamerone by Biosynthetic Rearrangement of an Aryl Diazoketone. Angew. Chem. Int. Ed. 48:767–770.
2. Winter, J. M.; Moffitt, M. C.; Zazopoulos, E.; McAlpine, J. B.; Dorrestein, P. C.; Moore, B. S. (2007) Molecular Basis for Chloronium-Mediated Meroterpene Cyclization: Cloning, Sequencing, and Heterologous Expression of the Napyradiomycin Biosynthetic Gene Cluster. J. Biol. Chem. 282:16362–16368.
1. Cifuentes, M.; Schilling, B.; Ravindra, R.; Winter, J.M.; Janik, M. E. (2006) Synthesis and Biological Evaluation of B-ring Modified Colchicines and Isocholchicine Analogs. Bioorg. Med. Chem. Lett. 16:2761–2764.