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Chemistry and Biology of Cys-based Redox Signaling

Our research is centered around developing chemical tools and methods to investigate Cys-based protein oxidation and regulations. We use various interdisciplinary approaches, including synthetic chemistry, protein biochemistry, molecular biology, cell biology, and mouse studies, to understand the protein chemistry behind redox biology.

1. Protein Glutathionylation in Physiology and Diseases

Our current research focused on the investigation of protein glutathionylation. Glutathionylation is the disulfide bond formation of a protein cysteine residue with intracellular glutathione that forms in response to oxidative stimuli. Many examples highlight the significance of protein glutathionylation in human health and disease.

Chemical Approach to Investigate Protein Glutathionylation

We are developing glutathione-based chemical probes to understand glutathione biology. We have previously developed an approach, called clickable glutathione, that labels glutathione with a clickable group to identify and characterize protein glutathionylation. The clickable group provides a chemical tag that allows for sensitive, selective, and versatile detection of glutathionylation. We are applying our approach for the identification of protein glutathionylation in cellular and mouse models. We also focus on the development of new chemoproteomic methods to study redox-based protein regulation.

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Chemical Proteomics and Bioinformatics for Identification of Protein Glutathionylation

Mass spectrometry-based cysteine profiling is now well-established in identifying functional cysteines in the proteome. We use a chemoproteomic strategy with clickable glutathione to identify and quantify glutathionylation on specific cysteine sites. We analyze proteomic data with MS analysis, bioinformatic analysis, and structural analysis. Bioinformatic analyses identify proteins of biological significance associated with diseases or specific biological processes. Structural analyses provide a molecular hypothesis that proposes functional outcomes upon glutathionylation. Overall, chemoproteomics, bioinformatics, and structural analysis are combined to identify and pinpoint potential biologically or functionally important cysteines susceptible to glutathionylation.

Biological Models for Protein Glutathionylation 

Glutathionylation in Cardiomyocytes: Reactive oxygen species (ROS) are significant factors contributing to heart and muscle diseases. We apply our strategy to understand glutathionylation in cardiomyocytes. This project aims to interrogate an interplay between ROS, glutathionylation, and sarcomere dysfunction. In this project, our major goal is to identify important cardiac or sarcomeric proteins susceptible to glutathionylation and characterize functional outcomes of glutathionylation on sarcomeric proteins

Glutathionylation in Cell Migration: Cell migration is a fundamental process in the development and maintenance of organisms, such as embryonic development, wound healing, and inflammation. Deregulated cell migration plays a crucial role in many diseases, including chronic wound and cancer metastasis. Many lines of evidence support that hydrogen peroxide or ROS are a crucial driver of cell migration via induction of protein cysteine oxidations. In this project, our major goal is to identify cysteines susceptible to glutathionylation during cell migration and analyze their regulatory roles in cell migration.

2. Biochemistry of Enzymes in Redox Regulation

Redox homeostasis is maintained and regulated by a balance of oxidases and redox enzymes that produce and remove the reactive species, respectively. Therefore, altered expression and/or activities of oxidases and redox enzymes directly contributed to dysregulated redox states associated with various pathophysiology. We are interested in understanding the biochemistry of oxidases in terms of their structure, biological function, and regulation with the ultimate goal of developing a therapeutic strategy.

3. Glutathione Derivatives as Chemical Tools in Medicine

Glutathione is a tripeptide, the major abundant thiol, typically known for its canonical role in buffering the redox state and maintaining redox homeostasis. However, the emerging examples support its non-canonical roles, beyond the redox function, in regulating specific proteins with therapeutic potential. We are interested in developing glutathione derivatives as chemical tools for understanding the non-canonical roles of glutathione with potential therapeutic direction.    

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