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.
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.
|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|
|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|
|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|
|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|
|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|
|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|
|Sato, Michio; Winter, Jaclyn M; Kishimoto, Shinji et al. (2016) Combinatorial Generation of Chemical Diversity by Redox Enzymes in Chaetoviridin Biosynthesis. Org Lett 18:1446-9|
|Zhang, Jinru; Liu, Nicholas; Cacho, Ralph A et al. (2016) Structural basis of nonribosomal peptide macrocyclization in fungi. Nat Chem Biol 12:1001-1003|
|Yu, Xia; Liu, Fang; Zou, Yi et al. (2016) Biosynthesis of Strained Piperazine Alkaloids - Uncovering the Concise Pathway of Herquline A. J Am Chem Soc :|
Showing the most recent 10 out of 46 publications