The Program Project goals towards the discovery and characterization of novel phosphonates have benefited significantly from biochemical and structural biological characterization oif the enzymes involved in the biosynthesis of these natural products. Additionally, detailed knowledge of the three dimensional structures of such enzymes in complex with their cognate substrates/inhibitors can aid in the engineering of these catalysts to yield derivative compounds with improved biological and/or pharmacokinetic properties. In this next cycle, we expand our research aims towards the biochemical characterization of gene clusters involved in the biosynthesis of the antibacterial plumbemycin and the antifungal rhizoctlcin. The enzymes from these clusters direct the production of two natural products consisting of a common warhead (the threonine synthase inhibitor (Z)-L-2-amino-5-phosphono-3-pentenoic acid (APPA)) but with different peptide-based delivery vehicles. We will carry out in vitro reconstitution of individual enzymes from each of these clusters and utilize this knowledge for the producfion of addifional pepfidic and non-peptidic derivatives of APPA that can target a range of additional pathogenic organisms. Concurrently, we also aim to continue our structure-function studies of several of the biosynthetic enzymes that have been characterized during the initial cycle. Lastly, we will also characterize the mechanisms of resistance that are utilized by the producing organisms and may limit the biological utility of several phosphonates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM077596-07
Application #
8457038
Study Section
Special Emphasis Panel (ZRG1-BCMB-U)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$310,274
Indirect Cost
$105,652
Name
University of Illinois Urbana-Champaign
Department
Type
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Peck, Spencer C; van der Donk, Wilfred A (2017) Go it alone: four-electron oxidations by mononuclear non-heme iron enzymes. J Biol Inorg Chem 22:381-394
Olivares, Philip; Ulrich, Emily C; Chekan, Jonathan R et al. (2017) Characterization of Two Late-Stage Enzymes Involved in Fosfomycin Biosynthesis in Pseudomonads. ACS Chem Biol 12:456-463
Born, David A; Ulrich, Emily C; Ju, Kou-San et al. (2017) Structural basis for methylphosphonate biosynthesis. Science 358:1336-1339
Peck, Spencer C; Wang, Chen; Dassama, Laura M K et al. (2017) O-H Activation by an Unexpected Ferryl Intermediate during Catalysis by 2-Hydroxyethylphosphonate Dioxygenase. J Am Chem Soc 139:2045-2052
Zhang, Mingzi M; Qiao, Yuan; Ang, Ee Lui et al. (2017) Using natural products for drug discovery: the impact of the genomics era. Expert Opin Drug Discov 12:475-487
Si, Tong; Li, Bin; Comi, Troy J et al. (2017) Profiling of Microbial Colonies for High-Throughput Engineering of Multistep Enzymatic Reactions via Optically Guided Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry. J Am Chem Soc 139:12466-12473
Ren, Hengqian; Hu, Pingfan; Zhao, Huimin (2017) A plug-and-play pathway refactoring workflow for natural product research in Escherichia coli and Saccharomyces cerevisiae. Biotechnol Bioeng 114:1847-1854
Ren, Hengqian; Wang, Bin; Zhao, Huimin (2017) Breaking the silence: new strategies for discovering novel natural products. Curr Opin Biotechnol 48:21-27
Zhang, Mingzi M; Wong, Fong Tian; Wang, Yajie et al. (2017) CRISPR-Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters. Nat Chem Biol :
Wendt, Kristen E; Ungerer, Justin; Cobb, Ryan E et al. (2016) CRISPR/Cas9 mediated targeted mutagenesis of the fast growing cyanobacterium Synechococcus elongatus UTEX 2973. Microb Cell Fact 15:115

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