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

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1GM106413-02
Application #
8549277
Study Section
Special Emphasis Panel (ZGM1-NDPA-A (01))
Program Officer
Gerratana, Barbara
Project Start
2012-09-30
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$746,900
Indirect Cost
$261,900
Name
University of California Los Angeles
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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
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
Bond, Carly; Tang, Yi; Li, Li (2016) Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases. Fungal Genet Biol 89:52-61

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