In the previous grant period, our enzymology and synthetic chemistry studies complemented the genetic and biochemical efforts towards understanding the biosynthetic logic of natural product phosphonates. The program project team has made significant progress, developing effective methods to detect new phosphonate biosynthetic gene clusters and understanding in great detail the biosynthetic pathways leading towards commercially important phosphonates such as phosphinothricin and fostomycin. As the genetic and biochemical studies became more efficient, a new bottleneck was identified that involves inefficient purification strategies and hence slow-down of structure elucidation of the products of newly discovered gene clusters. Part of the proposed studies in this subproject will focus on the development of efficient methods for purification and structural elucidation of those new compounds. In addition, the genome sequencing efforts of the past grant period identified cases in which the same natural product is made in different organisms by very different biosynthetic routes. We will investigate these examples of convergent evolution. Finally, many natural product phosphonates are produced as short peptides to promote uptake by peptide permeases in the target organisms. Whereas for some compounds small non-ribosomal peptide synthetase (NRPS) clusters are responsible for peptide bond formation, many phosphonate containing peptides are assembled in different, often unidentified ways. We will attempt to provide more insight into this very important aspect with respect to possible future engineering efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM077596-06
Application #
8329252
Study Section
Special Emphasis Panel (ZRG1-BCMB-U (40))
Project Start
2007-04-10
Project End
2017-03-31
Budget Start
2012-04-10
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$302,274
Indirect Cost
$103,299
Name
University of Illinois Urbana-Champaign
Department
Type
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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