Chemical biology for exploring the redox regulation and signaling pathways.

Regulation of cellular redox environment is important for normal cellular physiology. Therefore, alteration of cellular redox environment is known to induce different biological states of cells, including proliferation, differentiation, and apoptosis. The reactive oxygen and nitrogen species (ROS and RNS) generated from various sources, including mitochondrial activity and enzymes, are the major factor that can perturb the redox environment of cells.

Among multiple roles of ROS and RNS, it is increasingly recognized that ROS and RNS can be transiently generated in physiological conditions in response to various stimuli and they act as signaling molecules in redox signaling that regulates diverse cellular processes. In such condition, ROS and RNS are often sensed by the unique redox chemistry of thiol in a protein cysteine residue that undergoes various types of oxidative modifications, such as S-glutathionylation, sulfenylation, S-nitrosylation, and disulfide bond formation (Picture below). Importantly, these oxidative cysteine modifications profoundly influence physiological functions of many proteins, serving as a regulatory switch of many cellular processes.

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ROS, RNS, and protein cysteine modifications
 

We are interested in developing various biochemical tools and methods that can lead us to understanding the functional roles of ROS and RNS in regards to protein cysteine modifications.

Chemical tools for studying oxidative protein modification
We are developing chemical methods that lead to identifying various protein cysteine modifications in response to ROS or RNS. We are applying these tools to analyze such protein modifications in pathophysiological cellular conditions.

Biochemical studies for understanding oxidative protein modification
We are applying or developing biochemical methods for studying oxidative protein modifications. In this approach, we focus on evaluating structural and functional alterations of oxidative protein modification by various biochemical, biophysical methods and cell-based systems.

Small molecules that perturb the redox regulation and signaling.

The aberrant redox regulation, such as increased ROS and RNS, or up- and down-regulated redox enzymes, often leads to the imbalance between the generation and the removal of ROS and RNS, which correlates with many disease conditions, including diabetes, cancer, cardiovascular and neurodegenerative disease. We are interested in developing small-molecules or peptides that activate or inhibit the redox signaling enzymes and proteins. One includes the anti-oxidant response pathways regulated by Keap1-Nrf2. Many studies indicate that activation of this pathway provide the potential protection against disease conditions that involve oxidative stress, such as cancer and neurodegeneration. We are interested in developing and applying small molecules that perturb the redox control of cells.