个人简介

Defense Advanced Research Projects Agency (DARPA) Young Faculty Award, 2009; Camille and Henry Dreyfus New Faculty Award, 2006; NIH Postdoctoral Fellow, 2004; American Foundation for Pharmaceutical Education Gateway Fellowship, 1995-1997

研究领域

Biochemistry/Chemical and Biological Imaging/Chemical Biology/Organic Chemistry

Nature has provided us with an arsenal of agents that have proven clinically useful in the treatment of many human diseases, and this is particularly apparent for infectious diseases and cancer. Resistance to current anticancer and antimicrobial chemotherapies will always necessitate the discovery and development of additional therapeutic compounds, both by screening of natural products and by synthetic design. Biosynthetic engineering is a promising tool that could be coupled with these proven techniques to generate novel bioactive metabolites. Dr. Kelly's group examines natural products biosynthesis and its applications from chemical and microbiological perspectives. A number of naturally occurring antibiotics are biosynthesized by one of two classes of large, multimodular, often multi-enzyme complexes: either nonribosomal peptide synthetases (NRPSs) or polyketide synthases (PKSs). For every extender unit incorporated into the final product, there is a corresponding module in the PKS or NRPS. The modules are further subdivided into discrete catalytic and structural domains that each catalyze a single chemical step required to incorporate a monomeric unit into the polyketide or nonribosomal peptide. Following generation of a core skeleton, additional enzymatic transformations may be required for the bioactivity of the final metabolite. The modular NRPS and PKS systems are extremely attractive targets for biochemical and genetic manipulation to generate novel bioactive metabolites, and a body of work has emerged supporting the feasibility of this application. Before full exploitation of these approaches can be realized, a thorough understanding of the enzymes of interest and factors contributing to catalysis is paramount. Dr. Kelly's group is interested in the biosynthesis of polyketide and nonribosomal peptide antibiotics in addition to the biosynthesis of post-translationally modified peptide antibiotics. We aim to understand the assembly of central scaffolds that appear in families of metabolites that vary in their biological activity according to unique peripheral modifications. This requires a detailed understanding of the enzymes responsible for construction of these molecules, including their catalytic mechanism and substrate specificity. Strategies and techniques from organic chemistry, biochemistry, molecular biology, and microbiology will be infused together to accomplish this task. Ultimately, we will apply the information gleaned from these studies to direct the biosynthesis of designer metabolites possessing antimicrobial or anticancer activities.

近期论文

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Kathryn R. Rommel, Chaoxuan Li, and Wendy L. Kelly (2011) Identification of a Tetraene-Containing Product of the Indanomycin Biosynthetic Pathway. Org. Lett. 13, 2536-2539. DOI: 10.1021/ol200570u Chaoxuan Li, Feifei Zhang, and Wendy L. Kelly (2011) Heterologous production of thiostrepton and biosynthetic engineering of thiostrepton analogs Mol. Biosyst. 7, 82-90. DOI:10.1039/C0MB00129E Chaoxuan Li, Wendy L. Kelly (2010) Recent advances in thiopeptide antibiotic biosynthesis. Nat. Prod. Rep. 27, 153-164. DOI: 10.1039/b922434c Chaoxuan Li, Kathryn E. Roege, and Wendy L. Kelly (2009) Analysis of the Indanomycin Biosynthetic Gene Cluster from Streptomyces antibioticus NRRL 8167. ChemBioChem 10, 1064-1072. DOI: 10.1002/cbic.200800822 Wendy L. Kelly, Lisa Pan, and Chaoxuan Li (2009) Thiostrepton Biosynthesis: Prototype for a New Family of Bacteriocins, J. Am. Chem. Soc. 131, 4327-4334. DOI: 10.1021/ja807890a Kathryn E. Roege and Wendy L. Kelly (2009) Biosynthetic Origins of the Ionophore Antibiotic Indanomycin. Org. Lett. 11, 297-300. DOI: 10.1021/ol802422n Wendy L. Kelly (2008) Intramolecular Cyclizations of Polyketide Biosynthesis: Mining for a “Diels-Alderase?” Org. Biomol. Chem. 6, 4483-4493. DOI: 10.1039/b814552k Wendy L. Kelly, Michael T. Boyne II, Ellen Yeh, David A. Vosburg, Danica Galonić, Neil L. Kelleher, Christopher T. Walsh (2007) Characterization of the Aminocarboxycyclopropane-Forming Enzyme CmaC. Biochemistry, 46, 359-368. DOI: 10.1021/bi061930j Wendy L. Kelly, Nathan J. Hillson, and Christopher T. Walsh (2005) Excision of the Epothilone Synthetase B Cyclization Domain and Demonstration of in Trans Condensation/Cyclodehydration Activity, Biochemistry, 44, 13385-13393. DOI: 10.1021/bi051124x Wendy L. Kelly and Craig A. Townsend (2005) Mutational Analysis of nocK and nocL in the Nocardicin A Producer Nocardia uniformis, J. Bact. 187, 739-746. DOI: 10.1128/JB.187.2.739-746.2005 Wendy L. Kelly and Craig A. Townsend (2004) Mutational Analysis and Characterization of Nocardicin C-9′ Epimerase, J. Biol. Chem. 279, 38220-38227. DOI: 10.1074/jbc.M405450200 Wendy L. Kelly and Craig A. Townsend (2002) Role of the Cytochrome P450 NocL in Nocardicin A Biosynthesis. J. Am. Chem. Soc. 124, 8186-8187. DOI: 10.1021/ja025926g Jing Zhou, Wendy L. Kelly, Brian O. Bachmann, Michele Gunsior, Craig A. Townsend, and Edward I. Solomon (2001) Spectroscopic Studies of Substrate Interactions with Clavaminate Synthase 2, a Multifunctional α-KG-Dependent Non-Heme Iron Enzyme: Correlation with Mechanisms and Reactivities. J. Am. Chem. Soc. 123, 7388-7398. DOI: 10.1021/ja004025+ T. Mark Zabriskie, Wendy L. Kelly, and Xi Liang (1997) Stereochemical Course of the Oxidation of L-Pipecolic Acid by the Flavoenzyme L-Pipecolate Oxidase. J . Am. Chem. Soc. 119, 6446-6447. DOI: 10.1021/ja970825h