Natural products and their derivatives have been rich sources for drug discovery; it has been estimated that more than 60% of the drugs that are in the market derive from natural sources. However, during the last three decades, research aimed at exploiting natural products for drug discovery has seriously declined, in part due to our limite capability in new natural product discovery and analogue production. Innovative technology for natural product purification, quantification, overproduction, and diversification is urgently neede to make a paradigm shift in the field of natural product research and to promote natural product-based drug discovery and development. As tagging natural products can address these challenging aspects of natural product research, this proposal seeks to develop a novel strategy that overcomes the limitations of known methods for tagging natural products with a bioorthogonal functionality. To this end, we will explore the unusual synthetic biology that living systems offer for bioorthogonal functionalities and develop general platforms for the in situ labeling of natural products, particularly complex natural products that are difficult to be synthesized or derivatized chemically. The success of this strategy will directly produce orthogonally functionalized natural product analogues that can be subjected to facile chemical modification for drug screening. More importantly, tagging natural products with a unique chemical handle will enable the visualization, enrichment, quantification, and mode of action study of natural products through bioorthogonal chemistry, and thus have a profound impact on our ability to address challenging questions in natural product biosynthesis, biology, and pharmacology. In addition, a novel natural product-based, quantitative, high-throughput screening method based on this tagging strategy is proposed here as a useful tool for evolving natural product biosynthetic enzymes that can efficiently function in specific pathways to produce natural product analogues in high titers. This screening method will be leveraged to understand and engineer the biosynthesis of several important families of natural products for new antibiotic and anticancer drug discovery. The proposed interdisciplinary project bridges multiple innovations in natural product biosynthesis, protein engineering, and bioorthogonal chemistry, and if successful, will vastly expand the natural product research toolkit and have broad impact in enzymology, biosynthesis, and medicine. It is therefore uniquely suited to the New Innovator Award with respect to its significance, novelty, and the investigator's record of innovativeness and creativity. This project has minimal overlap with other efforts in the research group, while providing good synergy with various research projects and fitting perfectly in one of our main research themes: to harness the power of enzymes towards the biosynthesis of natural products with ultimate applications in advancing human health.
Natural products have gained substantial consideration in the field of modern medicine on account of their wide range of therapeutic properties. Not only do they continue to be an important source of drugs used today, but they also show promise as scaffolds for the development of new more potent pharmaceutical agents in the future. By developing general platforms to label natural products in situ, we will promote the mode of action study of medicinally active natural products, and advance combinatorial biosynthesis of natural products to produce 'unnatural' natural products with improved pharmaceutical properties.
|Liu, Joyce; Kaganjo, James; Zhang, Wenjun et al. (2018) Investigating the bifunctionality of cyclizing and ""classical"" 5-aminolevulinate synthases. Protein Sci 27:402-410|
|Cai, Wenlong; Zhang, Wenjun (2018) Engineering modular polyketide synthases for production of biofuels and industrial chemicals. Curr Opin Biotechnol 50:32-38|
|Harris, Nicholas C; Born, David A; Cai, Wenlong et al. (2018) Isonitrile Formation by a Non-Heme Iron(II)-Dependent Oxidase/Decarboxylase. Angew Chem Int Ed Engl 57:9707-9710|
|Harris, Nicholas C; Sato, Michio; Herman, Nicolaus A et al. (2017) Biosynthesis of isonitrile lipopeptides by conserved nonribosomal peptide synthetase gene clusters in Actinobacteria. Proc Natl Acad Sci U S A 114:7025-7030|
|Herman, Nicolaus A; Kim, Seong Jong; Li, Jeffrey S et al. (2017) The industrial anaerobe Clostridium acetobutylicum uses polyketides to regulate cellular differentiation. Nat Commun 8:1514|
|Zhang, Wenjun; Liu, Joyce (2016) Recent Advances in Understanding and Engineering Polyketide Synthesis. F1000Res 5:|
|Zhu, Xuejun; Shieh, Peyton; Su, Michael et al. (2016) A fluorogenic screening platform enables directed evolution of an alkyne biosynthetic tool. Chem Commun (Camb) 52:11239-42|
|Liu, Joyce; Zhu, Xuejun; Zhang, Wenjun (2015) Identifying the Minimal Enzymes Required for Biosynthesis of Epoxyketone Proteasome Inhibitors. Chembiochem 16:2585-9|
|Zhu, Xuejun; Su, Michael; Manickam, Kadhirvel et al. (2015) Bacterial Genome Mining of Enzymatic Tools for Alkyne Biosynthesis. ACS Chem Biol 10:2785-93|
|Huang, Wei; Kim, Seong Jong; Liu, Joyce et al. (2015) Identification of the Polyketide Biosynthetic Machinery for the Indolizidine Alkaloid Cyclizidine. Org Lett 17:5344-7|