The Program Project goals towards the discovery and characterization of novel phosphonates have benefited significantly from biochemical and structural biological characterization of the enzymes involved in the biosynthesis of these natural products. Additionally, detailed knowledge of the threedimensional 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 production of additional peptidic 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 #
5P01GM077596-08
Application #
8634113
Study Section
Special Emphasis Panel (ZRG1-BCMB-U)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
8
Fiscal Year
2014
Total Cost
$321,527
Indirect Cost
$109,484
Name
University of Illinois Urbana-Champaign
Department
Type
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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