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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-U)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois Urbana-Champaign
United States
Zip Code
Zhao, Huimin; Medema, Marnix H (2016) Standardization for natural product synthetic biology. Nat Prod Rep 33:920-4
Chekan, Jonathan R; Cogan, Dillon P; Nair, Satish K (2016) Molecular Basis for Resistance Against Phosphonate Antibiotics and Herbicides. Medchemcomm 7:28-36
Zhang, Mingzi M; Wang, Yajie; Ang, Ee Lui et al. (2016) Engineering microbial hosts for production of bacterial natural products. Nat Prod Rep 33:963-87
Goering, Anthony W; McClure, Ryan A; Doroghazi, James R et al. (2016) Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer. ACS Cent Sci 2:99-108
Ulrich, Emily C; van der Donk, Wilfred A (2016) Cameo appearances of aminoacyl-tRNA in natural product biosynthesis. Curr Opin Chem Biol 35:29-36
Freestone, Todd S; Zhao, Huimin (2016) Combinatorial pathway engineering for optimized production of the anti-malarial FR900098. Biotechnol Bioeng 113:384-92
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
Luo, Yunzi; Enghiad, Behnam; Zhao, Huimin (2016) New tools for reconstruction and heterologous expression of natural product biosynthetic gene clusters. Nat Prod Rep 33:174-82
Peck, Spencer C; van der Donk, Wilfred A (2016) Go it alone: four-electron oxidations by mononuclear non-heme iron enzymes. J Biol Inorg Chem :
Blodgett, Joshua Av; Zhang, Jun Kai; Yu, Xiaomin et al. (2016) Conserved biosynthetic pathways for phosalacine, bialaphos and newly discovered phosphonic acid natural products. J Antibiot (Tokyo) 69:15-25

Showing the most recent 10 out of 99 publications