Mesecar, Andrew - Purdue University - Department of Biological Sciences

个人简介

BS in Chemistry (ACS), 1988, Purdue University; Ph.D. in Biochemistry, 1995, University of Notre Dame; Post-Doctorate, 1995-1998, University of California, Berkeley

研究领域

The main interest of the Mesecar lab is the Structure & Function of Enzymes of biomedical importance. One of our fundamental goals is to gain a deeper understanding into the roles of protein dynamics and conformational changes in the molecular recognition and catalytic processes and to exploit this knowledge for the design of small molecule drugs that target these enzymes. We are currently studying the structure and function of enzymes involved in cancer chemoprevention, cancer cell proliferation and bacterial and viral pathogenesis. We are actively involved in the discovery of both natural and synthetic compounds that can be used as anti-cancer, anti-viral and anti-bacterial therapeutics, as well as compounds that can prevent cancer and promote cell longevity. Due to the complex nature of enzymatic catalysis and molecular recognition, we routinely use a variety of state-of-the-art experimental approaches and tools from the fields of chemistry, biology and physics. Our main experimental tools are static and time-resolved X-ray crystallography, enzyme chemistry & kinetics, molecular biology, mass-spec proteomics, assay development and optimization, high-throughput screening and molecular modeling and cheminformatics. Our multi-faceted, multi-disciplinary, and integrated approach to the elucidation of the nature of enzymatic catalysis and molecular recognition is deemed to be the emerging model for scientific investigation and education in the twenty-first century. Our current projects in the lab include: (1) the roles of deubiquitinating enzymes (DUBs) in cancer and antagonism of the innate immune response and targeting DUBs for anti-cancer and antiviral drug development; (2) regulation of the Keap1-Cul3-Rbx1 E3 Ubiquitin ligase system in regulating the cellular concentrations of the transcription factor Nrf2 and hence activation of the anti-oxidant response element (ARE); (3) the structure, function and evolution of coronavirus papain-like and 3C proteases and developing therapeutics targeted at these enzymes; and (4) determining the structure and mechanisms of bacterial (e.g. tuberculosis and anthrax) adenylyltrasferase enzymes in the CoA, NAD, FAD and menaquinone biosynthesis and evaluating these enzymes as potential drug targets.

近期论文

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Hu, C., Eggler, A. L., Mesecar, A. D., van Breemen, R. B., . 2011. "Modification of Keap1 cyseine residues by sulforaphane". Chem Res Toxicol. 24: 515-521. Small, E., Eggler, A., Mesecar, A. D. 2010. "Development of efficient E. coli expression and purification system for a catalytically active, human Cullin3-RINGBox1 protein complex and elucidation of its quaternary structure with Deap1". Biochem Bio;hys Res Commun. 400: 471-475. Eggler, A. L., Small, E., Hannink, M., Mesecar, A. D. 2009. "Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1". Biochem J. 422: 171-180. McAdams, K., Casper, E. S., Matthew Haas, R., Santarsiero, B. D., Eggler, A. L., Mesecar, A., Halkides, C. J. 2008. "The structures of T87l phosphono-DheY and T87l/Y106W phosphono-CheY help to explain their binding affinities to the FliM and CheZ peptides". Arch Biochem Biophys. 479: 105-113. Holland, R., Hawkins, A. E., Eggler, A. L., Mesecar, A. D., Fabris, D., Fishbein, J. C. 2008. "Prospective type 1 and type 2 disulfides of Keap1 protein". Chem Res Toxicol. 21: 2051-2060. Eggler, A. L., Gay, K. A., Mesecar, A. D. 2008. "Molecular mechanisms of natural products in chemoprevention: induction of cytoprotective enzymes by Nrf2". Mol Nutr Food Res. 52: S84-94. Luo, Y., Eggler, A. L., Liu, D., Liu, G., Mesecar, A. D., van Breemen, R. B. 2007. "Sites of alkylation of human Keap1 by natural chemoprevention agents". J Am soc mass Spectrom. 18: 2226-2232. Eggler, A. L., Luo, Y., van Breemen, R. B., Mesecar, A. D. 2007. "Identification of the highly reactive cysteine 151 in the chemopreventive agent-sensor Keap1 protein is method-dependent". Chem Res Toxicol. 20: 1878-1884. Liu, G., Eggler, A. L., Dietz, B. M., Mesecar, A. D., Bolton, J. L., Pezzuto, J. M., van Breemen, R. B. 2005. "Screening method for the discovery of potential cancer chemoprevention agents based on mass spectrometric detection of alkylated Keap1". Anal Chem. 77: 6407-6414. Eggler, A. L., Liu, G., Pezzuto, J. M., van Breemen, R. B., Mesecar, A. D. 2005. "Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2". Proc Natl Acad Sci USA. 102: 10070-10075. Dietz, B. M., Kang, Y. H., Liu, G., Eggler, A. L., Yao, P., Chawick, L. R., Pauli, G. G., Farnsworth, N. R., Mesecar, A. D., van Breemen, R. B., Bolton, J. L. 2005. "Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase". Chem Res Toxicol. 18: 1296-1305.