Natural product biosynthesis, Microbial genetics, Targeted metagenomics
Since the discovery of penicillin in the 1920s, natural products have had an unmistakable impact on our health and have inspired us with their intricate chemical structures and fascinating underlying metabolic pathways. Historically, biochemical and genetic studies in these systems have focused on free-living, fast growing terrestrial organisms due to technological and laboratory constraints. However, the past 10-15 years have seen an explosion of new DNA sequencing technologies and molecular biological techniques that have, for the first time, allowed genetic access to more subtle and intricate ecosystems. Our work focuses on the discovery and heterologous expression of pathways and genes involved in the biosynthesis of metabolites from unique microbial sources. We use cutting-edge and classical techniques in biochemistry, microbiology, metagenomics, and mass spectrometry to investigate unconventional peptide-based metabolites and pathways invoking radical-mediated chemistry. All in all, our research aims to tackle the exponentially expanding genomic universe for the discovery of new enzymology and therapeutics.
Freeman, MF, Vagstad, AL, Piel, J (2016) "Polytheonamide Biosynthesis Showcasing the Metabolic Potential of Sponge-associated Uncultivated 'Entotheonella'" Curr. Opin. Chem. Biol. 31: 8-14.
Buller, AR, Freeman, MF, Schildbach, JF, Townsend, CA (2014) "Exploring the Role of Conformational Heterogeneity in cis-Autoproteolytic Activation of ThnT" Biochemistry 53(26): 4273-4281.
Morinaka, BI, Vagstad, AL, Helf, MJ, Gugger, M, Kegler, C, Freeman, MF, Bode, HB, Piel, J (2014) "Radical SAM Epimerases Regioselectively Introduce Diverse d-Amino Acid Patterns into Peptide Natural Products" Angew. Chem. Int. Ed. 53(32): 8503-8507.
Cai, X, Teta, R, Kohlhass, C, Cruesemann, M, Ueoka, R, Mangoni, A, Freeman, MF§, Piel, J§ (2013) “Manipulation of Regulatory Genes Reveals Complexity and Fidelity in Hormaomycin Biosynthesis” Chem. Biol. 20(6): 839-846.
Freeman, MF*, Gurgui, C*, Helf, MJ, Uria, AR, Oldham, NJ, Sahl, HG, Matsunaga, S, Piel, J (2012) “Metagenome Mining Reveals Polytheonamides as Modified Ribosomal Peptides” Science 338: 387-390. [Concentrates: Chem. Eng. News 2012 90(3): 26.]
Buller, AR, Freeman, MF, Wright, NT, Schildbach, JF, Townsend, CA (2011) “Insights into cis-Autoproteolysis Reveal a Reactive State Formed through Conformation Rearrangement” Proc. Natl. Acad. Sci. U.S.A. 109(7): 2308-2313.
Freeman, MF, Moshos, KA, Bodner, MJ, Li, R, Townsend, CA (2008) “Four Enzymes Define the Role of Coenzyme A in Thienamycin Biosynthesis” Proc. Natl. Acad. Sci. U.S.A. 105(32): 11128-11133. [Research Highlight: ACS Chem. Biol. 2008 3(9): 522.]