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VBI Provides Potential Targets to Diabetes Therapeutics

Virginia Bioinformatics Institute (VBI) Assistant Professor Biswarup Mukhopadhyay has provided important information for researchers designing drugs for type 2 diabetics in the// December 22, 2006, Journal of Biological Chemistry.

The information should in time help researchers to identify potential targets for docking inhibitors that will slow down, but not fully eliminate, the body's overproduction of glucose.

The study investigates ways to control the activity of phosphoenolpyruvate carboxykinase – a key enzyme involved in the metabolic pathway used by the human body to produce glucose. Phosphoenolpyruvate carboxykinase helps to control blood sugar levels during fasting. An overproduction of this enzyme, among other events, may lead to type 2 diabetes.

Mukhopadhyay remarked: "The research is a proof of concept study showing that it is possible to alter the activity of phosphoenolpyruvate carboxykinase without directly interfering with catalysis. Because the research pertains to surface residues on the protein molecule, this approach could be used to design a compound that can prevent the enzyme from participating in the overproduction of glucose in the liver of a person with type 2 diabetes."

He added: "Much work remains to be done to take this finding from proof of concept to a potential clinical application but we have at least demonstrated that the activity of the enzyme can be modulated by structural manipulation."

The group investigated the roles of three key amino acid residues and, more specifically, examined how changing each residue affected the enzyme's properties. The researchers concluded that it is possible to influence the activity of the enzyme from a site distinct from where the reaction takes place on the enzyme.

The research appeared in the article, "Roles of Asp75, Asp78, and Glu83 of GTP-dependent phosphoenolpyruvate carboxykinase from Mycobacterium smegmatis," by Christ opher L. Case, Edward M. Concar, Kristin L. Boswell, and Biswarup Mukhopadhyay, in issue 281(51): 39 262–39 272 (

Case, Concar, and Boswell were all undergraduate students when they carried out the research. Case and Boswell were Virginia Tech biochemistry undergraduates who worked in Mukhopadhyay's research group at VBI, while Concar was a microbiology undergraduate at the University of Illinois at Urbana-Champaign, where Mukhopadhyay worked as a postdoctoral researcher. Concar now works in the biochemistry department of Genencor Inc. Boswell is currently a biochemistry graduate student at the University of Wisconsin.

Case, now a graduate student at Yale University, remarks: "I am better prepared to learn new techniques, plan experiments, and write scientific papers--three very important aspects of graduate and post-graduate research."

Mukhopadhyay commented: "The undergraduates made major contributions to the work, cloning, modifying, purifying and characterizing the enzyme, as well as performing kinetic experiments, secondary structure studies, and structural modeling."


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