Associate Professor of Medicinal Chemistry
Natural Product Biosynthesis, Genetic Engineering, Biocatalysts, Combinatorial Biosynthesis
Secondary metabolites are specialized small molecules produced in nature and often possessa 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.
- Heard, S. C. and Winter, J. M. (2022) Biosynthesis of the Fungal Nonribosomal Peptide Penilumamide A and Biochemical Characterization of a Pterin-Specific Adenylation Domain. Submitted
- Zhang, P.; Wu, G.; Heard, S. C.; Zhang, Y.; Winter, J. M. (2022) Genome Mining for Bifunctional Terpene Synthases in a Marine-Derived Fungus Unveils a Type I Diterpene Synthase Involved in Forming the Talarodiene 5-8-6 Tricyclic Ring System. Submitted Currently accessible via: https://www.biorxiv.org/content/10.1101/2022.05.03.490360v1
- Shin, Y-H.; Ban, Y. H.; Shin, J.; Park, I. W.; Yoon, S.; Ko, K.; Shin, J.; Nam, S-J.; Winter, J. M.; Kim, Y.; Yoon, Y. J.; Oh, D-C. (2021) Azetidine-Bearing Non-Ribosomal Peptides, Bonnevillamides D and E, Isolated from a Carrion Beetle-Associated Actinomycete. J Org Chem, 86, 11149-11159.
- Wu, G.; Dentinger, B. T. M.; Nielson, J. R.; Peterson, R. T.; Winter, J. M. (2021). Emerimicins V-X, 15 Residue Peptaibols Discovered from an Acremonium sp. through Integrated Genomic and Chemical Approaches. J Nat Prod, 84, 1113-1126.
- Kim, M-C.; Winter, J. M.; Cullum, R.; Zhifei, L.; Fenical, W. (2020). Complementary Genomic, Bioinformatics and Chemical Approaches Facilitate the Absolute Structure Assignment of Ionostatin, a Linear Polyketide from a Rare Marine-Derived Actinomycete. ACS Chem Biol, 15(9), 2507.
- Shang, Z.; Winter, J. M.; Kauffman, C. A.; Yang, I.; Fenical, W. (2019) Salinipeptins: Integrated Genomic and Chemical Approaches Reveal D-Amino Acid-Containing Ribosomally Synthesized and Post-Translationally Modified Peptides from a Great Salt Lake Streptomyces sp. ACS Chem Biol, 14(3), 415-425.
- Awan, A.R.; Winter, J. M.; Turner, D.; Shaw, W. M.; Suz, L. M.; Bradshaw, A. J.; Ellis, T.; Dentinger, B. T. M. (2018). Convergent Evolution of Psilocybin Biosynthesis by Psychedelic Mushrooms. bioRxiv, 374199 (doi: https://doi.org/10.1101/374199).
- Wu, G.; Nielson, J. R.; Peterson, R. T.; Winter, J. M. (2017). Bonnevillamides, Linear Heptapeptides Isolated from a Great Salt Lake-Derived Streptomyces sp. Mar Drugs, 15(7), 195.
- 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(31), 9885-9893.
- 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(14), 3774-3777.
- 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 Reveals Dual Functions of an Iterative Highly-Reducing Polyketide Synthase. J Am Chem Soc, 134(43), 17900-17903.
- Winter, J. M., & Moore, B. S. (2009). Exploring the Chemistry and Biology of Vanadium-Dependent Haloperoxidases. J Biol Chem, 284, (28), 18577-18581.
- 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 Engl, 48(4), 767-770.
- 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 (22), 16362-16368.