Due to increasing disease resistance to existing drugs and a dwindling pipeline of new drug leads, our need to generate chemical diversity is becoming ever more important. The best source to mine chemical diversity remains to be from natural products. In the post-genomics era, new approaches using the vast genomic information, as well as powerful tools in synthetic and chemical biology must be developed and applied towards the mining of natural chemical diversity. We believe that many of the microorganisms already identified and cultured contain far more biosynthetic potential than what has been tapped so far, and the manipulation of the known biosynthetic enzymes will lead to even more diversity than currently accessible. Therefore, capturing the full biosynthetic potential of Nature offers immense promise towards structural diversification and drug lead identification. In addition to discovering the natural products that have new structures and biological activities, it is equally important to identify new enzymes that responsible for generating the structural complexities. Compared to enzymes found in primary metabolism, biosynthetic enzymes catalyze significantly more diverse and complex transformations that lead to the dazzling structural features seen in the natural products. Therefore, complete understanding of the programming rules and enzymology of new enzymes discovered from the natural product pathways is needed. Deeper insight into the protein sequence-activity relationships of the enzymes can also enable more rational prediction of natural product structures from genome sequences, and can in turn further accelerate the genome mining efforts towards new natural products. In this proposal we will develop strategies to mine the chemical diversity encoded in filamentous fungi, discover the enzymes that give rise to the structural complexity and engineer enzymes into useful biocatalysts where applicable. We will 1) develop and apply new tools to explore genetically encoded chemical space from different filamentous fungi species based on phylogeny and bioecological niche; 2) develop and validate a target-guided mining approach that connects genomics-based mining to clinically relevant biological activity; 3) perform biochemical characterization of enzymes in fungal biosynthetic pathways to establish sequence- activity relationships. Programming rule of PKS will be studied, as well as those of oxidative enzymes; and 4) perform structure-guided and evolutionary engineering of proteins discovered from biosynthetic pathways towards becoming useful biocatalysts.

Public Health Relevance

Natural products and natural product-derived drugs have been indispensible towards the treatment of different diseases and the prophylactic maintenance of healthy lifestyle. In this proposal, we aim to significantly expand the chemical diversity of natural product using genomic-based and protein engineering approaches.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZGM1)
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Bond, Michelle Rueffer
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University of California Los Angeles
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
Los Angeles
United States
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Yan, Yan; Liu, Qikun; Zang, Xin et al. (2018) Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action. Nature 559:415-418
Hai, Yang; Tang, Yi (2018) Biosynthesis of Long-Chain N-Acyl Amide by a Truncated Polyketide Synthase-Nonribosomal Peptide Synthetase Hybrid Megasynthase in Fungi. J Am Chem Soc 140:1271-1274
Walsh, Christopher T; Tu, Benjamin P; Tang, Yi (2018) Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism. Chem Rev 118:1460-1494
Jamieson, Cooper S; Ohashi, Masao; Liu, Fang et al. (2018) The expanding world of biosynthetic pericyclases: cooperation of experiment and theory for discovery. Nat Prod Rep :
Kishimoto, Shinji; Hara, Kodai; Hashimoto, Hiroshi et al. (2018) Enzymatic one-step ring contraction for quinolone biosynthesis. Nat Commun 9:2826
Gao, Shu-Shan; Zhang, Tao; Garcia-BorrĂ s, Marc et al. (2018) Biosynthesis of Heptacyclic Duclauxins Requires Extensive Redox Modifications of the Phenalenone Aromatic Polyketide. J Am Chem Soc 140:6991-6997
Walsh, Christopher T; Tang, Yi (2018) Recent Advances in Enzymatic Complexity Generation: Cyclization Reactions. Biochemistry 57:3087-3104
Li, Li; Tang, Man-Cheng; Tang, Shoubin et al. (2018) Genome Mining and Assembly-Line Biosynthesis of the UCS1025A Pyrrolizidinone Family of Fungal Alkaloids. J Am Chem Soc 140:2067-2071
Tang, Man-Cheng; Cui, Xiaoqing; He, Xueqian et al. (2017) Late-Stage Terpene Cyclization by an Integral Membrane Cyclase in the Biosynthesis of Isoprenoid Epoxycyclohexenone Natural Products. Org Lett 19:5376-5379
Hang, Leibniz; Tang, Man-Cheng; Harvey, Colin J B et al. (2017) Reversible Product Release and Recapture by a Fungal Polyketide Synthase Using a Carnitine Acyltransferase Domain. Angew Chem Int Ed Engl 56:9556-9560

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