John J. Mieyal, PhD
Professor, Pharmacologyjjm5@case.edu 216.368.3383 (o) 216.368.3395 (f)
Modulation of the thiol-disulfide status of critical cysteine residues on proteins is becoming recognized as an important mechanism of oxidative signal transduction as well as an important consequence of oxidative stress associated with aging and various disease states, including cardiovascular and neurodegenerative diseases, diabetes, AIDS, and cancer. Within these various contexts, a prevalent form of cysteine modification is reversible formation of protein mixed disulfides (protein-SSG) with intracellular glutathione (GSH).
Our laboratory is focused on the molecular mechanisms and physiological implications of enzymes that catalyze thiol-disulfide oxidoreductase (TDOR) reactions. In particular, we have characterized glutaredoxin (thioltransferase) as the TDOR enzyme that displays specificity and high catalytic efficiency for protein-SSG substrates, including hemoglobin-SSG, NF1-SSG, HIV-protease-SSG, and actin-SSG. This realization has placed made glutaredoxin a focal point in advancing understanding of protein-S-glutathionylation as a regulatory mechanism akin to phosphorylation of proteins. We are employing a range of cellular, molecular, and structural biology approaches to delineate the molecular basis for glutaredoxin catalysis and its role in regulation of fundamental cellular processes like proliferation, differentiation and apoptosis. A key objective in our research program is to characterize also the mechanisms of formation of specific protein-SSG intermediates and identify the enzymes responsible for catalyzing these reactions within cells. We are also focused on delineating changes in the regulation of protein-SSG status of specific effector proteins associated with the various disease states that involve oxidative stress.