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SPECTROSCOPIC CHARACTERIZATION OF ZINC HYDROLASES NDM-1 AND MMP-1 FOR DRUG DISCOVERY

yang, hao
http://rave.ohiolink.edu/etdc/view?acc_num=miami1437835452

Abstract Details

2015, Doctor of Philosophy, Miami University, Chemistry and Biochemistry.
A myriad of zinc hydrolases have been recognized as biochemically-important targets for different diseases; however, structural and functional studies on these enzymes are often hindered by the spectroscopically-silent Zn(II) ion. Herein, Co(II) was used as a molecular beacon for Zn(II) in di-zinc hydrolases NDM-1 (a drug target for bacterial infection diseases) and MMP-1 (a drug target for cancer metastasis, arthritis, and vascular diseases), and the Co(II)-substituted analogs were used to extract structural/functional information. The interpretation of spectroscopic studies on mononuclear Co(II)-substituted zinc-hydrolases is straightforward compared to the interpretation of similar studies on di-zinc hydrolases, due to overlapping spectroscopic features in the spectra. Therefore, heterodimetallic analogs of NDM-1 (Zn1Co2 and Co1Cd2) and MMP-1 (CoCZnS), with a Co(II) probe at one metal site and a diamagnetic metal at the other, were generated and characterized with a suite of spectroscopic techniques, including CD, UV-Vis, EPR, 1H NMR, and XAS. These analogs allowed for the structural and functional interrogation of each individual metal site. The catalytic mechanism of NDM-1 was dissected by combining steady-state, pre-steady state, and rapid freeze-quenched spectroscopic studies, which lead to a potential new class of mechanism-based inhibitors. Mechanistic and structural studies on MMP-1 revealed insight about the binding of known ZBGs in the enzyme’s active site, which provides information for the design of future selective inhibitors. The long-term goal of this dissertation was to establish a common methodology of using a Co(II) probe to explore the structure/function of biochemically-important di-zinc-hydrolases.
Michael Crowder (Advisor)
David Tierney (Committee Chair)
158 p.
Biochemistry; Chemistry
Metallo-beta-lactamase, NDM-1, MMP-1, spectroscopy, drug discovery, zinc binding group

Recommended Citations

Citations

  • yang, H. (2015). SPECTROSCOPIC CHARACTERIZATION OF ZINC HYDROLASES NDM-1 AND MMP-1 FOR DRUG DISCOVERY [Doctoral dissertation, Miami University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=miami1437835452

    APA Style (7th edition)

  • yang, hao. SPECTROSCOPIC CHARACTERIZATION OF ZINC HYDROLASES NDM-1 AND MMP-1 FOR DRUG DISCOVERY. 2015. Miami University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=miami1437835452.

    MLA Style (8th edition)

  • yang, hao. "SPECTROSCOPIC CHARACTERIZATION OF ZINC HYDROLASES NDM-1 AND MMP-1 FOR DRUG DISCOVERY." Doctoral dissertation, Miami University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=miami1437835452

    Chicago Manual of Style (17th edition)

miami1437835452
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© 2015, some rights reserved.Creative Commons License SPECTROSCOPIC CHARACTERIZATION OF ZINC HYDROLASES NDM-1 AND MMP-1 FOR DRUG DISCOVERY by hao yang is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Miami University and OhioLINK.