Using enzymes that possess exquisite and diverse catalytic power, an enormous array of complex natural products (NPs) is synthesized across the different kingdoms. The vast chemical diversity, especially of NPs from plants and microorganisms, contributes to the wide range of useful biological activities displayed by NPs. Collectively, NP and NP-derived drugs have been indispensible towards the treatment of different diseases and the prophylactic maintenance of healthy lifestyle. 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 NPs. While traditional, phenotype-based screening of NP from organisms found in esoteric parts of the world continues to be a source of new chemical entities, it has become clear that new approaches using the vast genomic information, as well as powerful tools in chemical biology can be applied towards the rediscovery of natural chemical diversity, starting from the wealth of NP biosynthetic information accumulated to date. Essentially, 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. In this proposal, we will use two approaches to rediscover the chemical diversity from Nature. First, we will use genomics driven methods to discover the majority of NPs that are encoded, but not synthesized by microorganisms during normal cultivating conditions. Synthetic biology strategies in both the native and heterologous hosts will be developed to fully realize the biosynthetic potential of known organisms. Second, we will develop protein engineering strategy to evolve known biosynthetic enzymes towards generation of new chemical diversity. A three component metabolite-sensitive circuitry will be constructed to allow coupling of metabolite structure diversity to cellular phenotype. Together, our proposed work here will fully harvest and expand the amazing chemical diversity present in Mother Nature.

Public Health Relevance

Natural product 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)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1 (01))
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Gerratana, Barbara
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University of California Los Angeles
Engineering (All Types)
Schools of Engineering
Los Angeles
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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
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
Kishimoto, Shinji; Hara, Kodai; Hashimoto, Hiroshi et al. (2018) Enzymatic one-step ring contraction for quinolone biosynthesis. Nat Commun 9:2826
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
Gao, Shu-Shan; Garcia-Borràs, Marc; Barber, Joyann S et al. (2017) Enzyme-Catalyzed Intramolecular Enantioselective Hydroalkoxylation. J Am Chem Soc 139:3639-3642
Ohashi, Masao; Liu, Fang; Hai, Yang et al. (2017) SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis. Nature 549:502-506
Liu, Nicholas; Hung, Yiu-Sun; Gao, Shu-Shan et al. (2017) Identification and Heterologous Production of a Benzoyl-Primed Tricarboxylic Acid Polyketide Intermediate from the Zaragozic Acid A Biosynthetic Pathway. Org Lett 19:3560-3563
Zou, Yi; Garcia-Borràs, Marc; Tang, Mancheng C et al. (2017) Enzyme-catalyzed cationic epoxide rearrangements in quinolone alkaloid biosynthesis. Nat Chem Biol 13:325-332
Sato, Michio; Dander, Jacob E; Sato, Chizuru et al. (2017) Collaborative Biosynthesis of Maleimide- and Succinimide-Containing Natural Products by Fungal Polyketide Megasynthases. J Am Chem Soc 139:5317-5320
Grandner, Jessica M; Cacho, Ralph A; Tang, Yi et al. (2016) Mechanism of the P450-Catalyzed Oxidative Cyclization in the Biosynthesis of Griseofulvin. ACS Catal 6:4506-4511

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