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 fosfomycin. 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 #
5P01GM077596-09
Application #
8828224
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Type
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Ulrich, Emily C; Bougioukou, Despina J; van der Donk, Wilfred A (2018) Investigation of Amide Bond Formation during Dehydrophos Biosynthesis. ACS Chem Biol 13:537-541
Wang, Bin; Guo, Fang; Dong, Shi-Hui et al. (2018) Activation of silent biosynthetic gene clusters using transcription factor decoys. Nat Chem Biol :
Goettge, Michelle N; Cioni, Joel P; Ju, Kou-San et al. (2018) PcxL and HpxL are flavin-dependent, oxime-forming N-oxidases in phosphonocystoximic acid biosynthesis in Streptomyces. J Biol Chem 293:6859-6868
Sun, H; Zhao, H; Ang, E L (2018) A coupled chlorinase-fluorinase system with a high efficiency of trans-halogenation and a shared substrate tolerance. Chem Commun (Camb) 54:9458-9461
McLaughlin, Martin I; van der Donk, Wilfred A (2018) Stereospecific Radical-Mediated B12-Dependent Methyl Transfer by the Fosfomycin Biosynthesis Enzyme Fom3. Biochemistry 57:4967-4971
Wang, Yajie; Ren, Hengqian; Zhao, Huimin (2018) Expanding the boundary of biocatalysis: design and optimization of in vitro tandem catalytic reactions for biochemical production. Crit Rev Biochem Mol Biol 53:115-129
Parkinson, Elizabeth I; Tryon, James H; Goering, Anthony W et al. (2018) Discovery of the Tyrobetaine Natural Products and Their Biosynthetic Gene Cluster via Metabologenomics. ACS Chem Biol 13:1029-1037
Born, David A; Ulrich, Emily C; Ju, Kou-San et al. (2017) Structural basis for methylphosphonate biosynthesis. Science 358:1336-1339
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
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

Showing the most recent 10 out of 119 publications