Natural products and their derivatives continue to play an important role in the drug pipeline. Over time, 7000 known structures have led to more than 20 commercial drugs, and about half of the new drugs approved in the last decade are based on natural products. Screening of new natural products and their analogs will continue, and be enhanced by modern methods such as metabolic engineering, synthetic biology, and structural analysis of compounds and the enzymes that produce them. For example, new biosynthetic routes are being built around engineered systems such as the modular polyketide synthases to produce new compounds. There are also still a tremendous number of new microbial natural products to be explored, as evidenced by the genomic sequencing data coming forth. Nevertheless, the discovery of new compounds remains an adventitious endeavor. Genome mining efforts to identify interesting clusters and to predict what natural products might come from these clusters of genes are beginning to produce hypotheses;however the homology of the enzymes to known enzymes is generally low. We propose to create a new partnership, named the Natural Products Partnership, within the PSI Biology Network framework to play strong joint roles in both the identification of new natural product pathways and the subsequent discovery of new natural product-based pharmaceuticals by revealing the structures and active sites of novel enzymes, characterizing the enzymatic reactions of the gene products, identifying new natural products and thus offering opportunities to identify and customize the pathways by altering specificities and/or identifying novel proteins or domains with desired enzymatic properties. The combination of the PSI Network Centers with their high-throughput structure determination capability and the biology-driven team of natural products scientists through the Natural Products Partnership are strongly positioned to create a high impact program. The experience of the structural biologists with PSI activities and their leadership in developing technologies and infrastructure in the PSI program will make a smooth transition to PSI Biology activities possible.
Natural products and their derivatives continue to play an important role in the drug pipeline, with many in actual use or in trials. Our proposed Natural Products Partnership will combine the high-throughput capabilities of the PSI Network with state-of-the-art natural product research to yield new leads and new reactions for creation of drug candidates.
|Chang, Chin-Yuan; Lohman, Jeremy R; Huang, Tingting et al. (2018) Structural Insights into the Free-Standing Condensation Enzyme SgcC5 Catalyzing Ester-Bond Formation in the Biosynthesis of the Enediyne Antitumor Antibiotic C-1027. Biochemistry 57:3278-3288|
|Chang, Chin-Yuan; Yan, Xiaohui; Crnovcic, Ivana et al. (2018) Resistance to Enediyne Antitumor Antibiotics by Sequestration. Cell Chem Biol 25:1075-1085.e4|
|Aoki, Scott T; Porter, Douglas F; Prasad, Aman et al. (2018) An RNA-Binding Multimer Specifies Nematode Sperm Fate. Cell Rep 23:3769-3775|
|Wang, Nan; Rudolf, Jeffrey D; Dong, Liao-Bin et al. (2018) Natural separation of the acyl-CoA ligase reaction results in a non-adenylating enzyme. Nat Chem Biol 14:730-737|
|Kupitz, Christopher; Olmos Jr, Jose L; Holl, Mark et al. (2017) Structural enzymology using X-ray free electron lasers. Struct Dyn 4:044003|
|Elshahawi, Sherif I; Cao, Hongnan; Shaaban, Khaled A et al. (2017) Structure and specificity of a permissive bacterial C-prenyltransferase. Nat Chem Biol 13:366-368|
|Hughes, Ryan R; Shaaban, Khaled A; Zhang, Jianjun et al. (2017) OleD Loki as a Catalyst for Tertiary Amine and Hydroxamate Glycosylation. Chembiochem 18:363-367|
|Annaval, Thibault; Rudolf, Jeffrey D; Chang, Chin-Yuan et al. (2017) Crystal Structure of Thioesterase SgcE10 Supporting Common Polyene Intermediates in 9- and 10-Membered Enediyne Core Biosynthesis. ACS Omega 2:5159-5169|
|Huber, Tyler D; Wang, Fengbin; Singh, Shanteri et al. (2016) Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways. ACS Chem Biol 11:2484-91|
|Helmich, Kate E; Pereira, Jose Henrique; Gall, Daniel L et al. (2016) Structural Basis of Stereospecificity in the Bacterial Enzymatic Cleavage of ?-Aryl Ether Bonds in Lignin. J Biol Chem 291:5234-46|
Showing the most recent 10 out of 48 publications