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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-BCMB-U (40))
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University of Illinois Urbana-Champaign
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Shao, Zengyi; Zhao, Huimin (2014) Manipulating natural product biosynthetic pathways via DNA assembler. Curr Protoc Chem Biol 6:65-100
Cobb, Ryan E; Ning, Jonathan C; Zhao, Huimin (2014) DNA assembly techniques for next-generation combinatorial biosynthesis of natural products. J Ind Microbiol Biotechnol 41:469-77
Luo, Yunzi; Cobb, Ryan E; Zhao, Huimin (2014) Recent advances in natural product discovery. Curr Opin Biotechnol 30:230-7
Doroghazi, James R; Albright, Jessica C; Goering, Anthony W et al. (2014) A roadmap for natural product discovery based on large-scale genomics and metabolomics. Nat Chem Biol 10:963-8
Yu, Xiaomin; Price, Neil P J; Evans, Bradley S et al. (2014) Purification and characterization of phosphonoglycans from Glycomyces sp. strain NRRL B-16210 and Stackebrandtia nassauensis NRRL B-16338. J Bacteriol 196:1768-79
Wang, Meng; Beissner, Mirko; Zhao, Huimin (2014) Aryl-aldehyde formation in fungal polyketides: discovery and characterization of a distinct biosynthetic mechanism. Chem Biol 21:257-63
Agarwal, Vinayak; Peck, Spencer C; Chen, Jui-Hui et al. (2014) Structure and function of phosphonoacetaldehyde dehydrogenase: the missing link in phosphonoacetate formation. Chem Biol 21:125-35
Ju, Kou-San; Doroghazi, James R; Metcalf, William W (2014) Genomics-enabled discovery of phosphonate natural products and their biosynthetic pathways. J Ind Microbiol Biotechnol 41:345-56
Eriksen, Dawn T; Lian, Jiazhang; Zhao, Huimin (2014) Protein design for pathway engineering. J Struct Biol 185:234-42
Cioni, Joel P; Doroghazi, James R; Ju, Kou-San et al. (2014) Cyanohydrin phosphonate natural product from Streptomyces regensis. J Nat Prod 77:243-9

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