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Access Type

WSU Access

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Young-Hoon Ahn

Abstract

Oxidative stress is a common characteristic of age-related diseases such as vascular diseases, diabetes and cancer. Many diseases are known to be regulated by glutathionylation. Glutathionylation is referred to as the formation of disulfide bond between a protein cysteine and a glutathione. To understand the molecular mechanisms behind the disease initiation and progression, identification of such glutathionylated proteins is important. Even though existing methods have been widely used, several limitations of these methods hinder the identification of such proteins in disease conditions. Therefore, we developed a versatile chemical method that generates clickable glutathione inside the cells. In this method, we generated a mutant form of glutathione synthetase (GS M4) to metabolically synthesize clickable glutathione for studying and identifying proteins in disease conditions. Using clickable glutathione approach, we uncovered a regulatory role of glucose metabolism in glutathionylation. Also, we have identified over 1400 of glutathionylated proteins in response to mitochondrial dysfunction and glucose deprivation, a common characteristic found in metabolic disorders. Moreover, we have identified several new glutathionylated proteins including ser/thr protein phosphatase 2Cα (PP2Cα). Further, we uncovered a new role for PP2Cα glutathionylation that promotes cancer cell migration through the activation of JNK in response to metabolic alterations.

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