Dr. Nin Dingra
Part - Time Faculty
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B.S Chemistry, Armstrong Atlantic State University, Savannah, GA (2005)
Ph.D Biochemistry, University of South Carolina, Columbia, SC (2010)
Elucidating the function of pseudophosphatases in S. Cerevisiae.
Posttranslational modification of proteins by reversible phosphorylation is a major mechanism of protein regulation in eukaryotic cells. Of all the proteins encoded by human genome, approximately one-third are presumed to be phosphorylated during their life cycle. The protein kinases and phosphatases catalyze this reversible modification and they often constitute integral components of signal transduction cascades that mediate cell proliferation, differentiation, and cell cycle control. Interference with the activity of these enzymes can potentially results in altered cellular function and development of diseases such as cancer, diabetes, and autoimmune disease.
The largest class of phosphatases by far are protein tyrosine phosphatases (PTPs) that dephosphorylate the phosphotyrosine amino acid residue. The PTP family also contains pseudophosphatases that possess the conserved domain of PTPs but are catalytically inactive because the reactive cysteine residue at the active site is replaced by another amino acid residue. These proteins are named STYX (for phosphor-Serine or Threonine or tYrosine interaction protein). A single point mutation that places cysteine residue at the catalytic site acquires the protein catalytic activity towards phospho-tyrosine and phospho-threonine. Moreover, sequence analysis suggests that Styx proteins resemble DSPs and possess all the structural components necessary for binding phosphorylated substrates by a mechanism similar to that of the DSPs.
Pseudophosphatases appear to have an important cellular function although they do not have hydrolytic activity towards the phosphoproteins. Despite their importance in cellular functioning, the actual mechanism of how these pseudo-phosphatases function is still not known. Our long-term research objective is to elucidate the function of pseudo-phosphatase proteins in the cell. This research aims at elucidating how yeast pseudo-phosphatase (Oca2p) regulates the phosphatase activity of its catalytically active counterparts. We will test our hypothesis by identifying interacting partners of Oca2p and determining how binding of Oca2p on its partners affect their catalytic activity using both in vitro and in vivo experiments. Saccharomyces cerevisiae,the most extensively characterized of the yeasts, has been used as a model for studying various biochemical pathways in eukaryotes. In fact, S. cerevisiae has been used in understanding the human disease genes that lead to the knowledge of pathophysiology of numerous human diseases. Since S. cerevisiae shares key molecules and biochemical pathways with higher eukaryotes, we will use this remarkable organism as our model in explaining the answers to our hypothesis.
Characterization of a new class of carbon monoxide releasing molecules.
Although carbon monoxide (CO) is well known as a poison in high concentrations, humans endogenously produce CO in a biochemical process mediated by a class of enzymes called heme oxygenases (HO). Categorized as a member of gasotransmitters together with Nitric oxide (NO) and hydrogen sulfide (H2S), CO has recently been reported to be important as a signaling molecule in the body. The majority of CO in our body is produced by enzymatic conversion of heme to CO, biliverdin, and ferrous iron. This reaction is catalyzed by heme oxygenases namely, HO-1, HO-2, and HO-3, that arefound throughout nature including algae, plants, bacteria and mammals.
Several roles of endogenous CO in physiological functions have been reported in literature. Evidences have shown that CO may act as a signaling molecule in many neuronal activities, including learning, memory, nociception, chemoreception, and odor response. Owed to its physiological importance, gaseous CO has been used as a therapeutic agent in medical applications. A few examples include hypertension, cardiac, renal and small bowel graft rejection, preservation of transplanted organs and other treatments. However, gaseous CO is not a desired long-term therapy due to the difficulty in administration to the desired places and the toxic effect for inhalation. As a consequence, a group of molecules that are capable of releasing CO, commonly referred to as carbon monoxide releasing molecules (CO-RMs), have been developed over the past decades. CO-RMs have several advantages over the conventional gaseous CO inhalation. First, the molecules can be tailored to increase water solubility so that the concentration can be higher than dissolved gaseous CO. Secondly, the amount of CO introduced into a patient's body can be controlled by administering the exact amount of CO-RMs. Thirdly, injection of these molecules into specific sites in the body is more feasible than the gaseous CO.
Many CO-RMs have been identified so far, but most are toxic and few have pharmacological activities in physiological conditions. Discovery of new and diverse CO-RM that is capable of releasing controlled amounts of CO in physiological conditions is highly desirable. Our research aims at preparing the novel molecules that release CO yet with low toxicity. Since the carboxyboranes demonstrate a high potential in pharmacological usage, our approach is to prepare the amino acid derivatives of the carboxyboranes that will have the same or better CO releasing effect and at the same time produce the natural amino acids as by-products to reduce toxicity. The final product of this research will be a host of new compounds for exploration as potential therapeutics.
2011 - Present: Assistant Professor, Columbus State University
2010 - 2011: Instructor, Armstrong Atlantic State University
2009 - 2010: NSF Graduate Teaching Fellow, University of South Carolina