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A Chemical Approach to Distinguish ATP-dependent Proteases

Fishovitz, Jennifer

Abstract Details

2011, Doctor of Philosophy, Case Western Reserve University, Chemistry.
Mammalian Lon and ClpXP are two ATP-dependent proteases that are found in the mitochondrial matrix and have been implicated in protecting the mitochondria against damage from oxidative stress. Our lab is interested in understanding the role of Lon and ClpXP in the regulation of levels of oxidatively damaged proteins. There has been shown to be a transient increase in ATP-dependent proteolysis activity following oxidative stress, but there has been no functional assay to distinguish between the activities of these two enzymes. Previously, genetic knock-down studies have been employed with similar proteases, but can lead to changes in cellular metabolism that obscure the accurate detection of substrates. Because Lon and ClpXP have been shown to have different peptide cleavage specificities in degrading protein substrates, I have developed a series of chemical tools which allow for the profiling these enzymes individually at a post-translational level. I now have enzyme-specific peptide substrates and enzyme-specific inhibitors that can be used to inactivate one protease while analyzing the activity of the other in order to identify their respective role in maintenance of mitochondrial function in healthy and oxidatively damaged tissue. These compounds are used in isolated mitochondria to monitor the activity of the individual protease. The information gathered in these studies will lead to the development of potent inhibitors of human Lon and ClpXP, specific peptide substrates, and a method to identify physiologically relevant protein substrates of each enzyme in normal and damaged mitochondria.
Irene Lee, PhD (Advisor)
Mary Barkley, PhD (Committee Chair)
Michael Zagorski, PhD (Committee Member)
Anthony Berdis, PhD (Committee Member)
Thomas Gerken, PhD (Committee Member)
130 p.

Recommended Citations

Citations

  • Fishovitz, J. (2011). A Chemical Approach to Distinguish ATP-dependent Proteases [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1291142553

    APA Style (7th edition)

  • Fishovitz, Jennifer. A Chemical Approach to Distinguish ATP-dependent Proteases. 2011. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1291142553.

    MLA Style (8th edition)

  • Fishovitz, Jennifer. "A Chemical Approach to Distinguish ATP-dependent Proteases." Doctoral dissertation, Case Western Reserve University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1291142553

    Chicago Manual of Style (17th edition)