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Archive - Nov 5, 2011

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N-Terminal Acetylation Promotes Some Protein Interactions; Cancer Drug Implications

Research led by St. Jude Children's Research Hospital scientists has identified an unexpected mechanism facilitating some protein interactions that are the workhorses of cells and, in the process, identified a potential new cancer drug development target. The discovery involves a chemical known as an acetyl group. An estimated 85 percent of human proteins have this chemical added to the amino acid at one end of the protein. The addition comes in a process known as N-terminal acetylation. N-terminal acetylation occurs shortly after proteins are assembled. Although it has long been known that proteins are N-terminally acetylated, until now it was unknown how such acetylation could serve specific functions. The findings came from scientists studying a system cells use to regulate the fate and function of proteins. The researchers showed that much like a key must fit precisely to work a lock, the acetylated end of one enzyme fits perfectly into a deep pocket on the surface of another protein. The connection helps accelerate the activity of a protein complex that is involved in regulating cell division and that has been linked to cancer. The research appears in the November 4, 2011 issue of the journal Science. The findings have potential implications for drug discovery and for understanding basic mechanisms governing the interaction of possibly thousands of proteins, said the study's senior author, Dr. Brenda Schulman, a member of the St. Jude Department of Structural Biology and a Howard Hughes Medical Institute investigator. "The work presents a major new concept in protein-protein interactions," she said.

Blocking Key Enzyme May Protect Against Kidney Disease in Diabetes

The enzyme arginase-2 plays a major role in kidney failure, and blocking the action of this enzyme might lead to protection against renal disease in diabetes, according to researchers. "We believe these arginase inhibitors may be one of the new targets that can slow down the progression of, or even prevent the development of, end-stage renal disease," said Dr. Alaa S. Awad, assistant professor of nephrology, Penn State College of Medicine. In the United States, diabetes is the leading cause of end-stage renal disease -- kidney failure -- causing nearly 45 percent of all cases. Currently the treatment for diabetic patients likely to develop end-stage renal disease includes blood pressure and glucose control therapy and life-style changes. The researchers tested two different sets of diabetic mice to try to prevent kidney failure. They gave one set of mice -- genetically diabetic -- a potent arginase inhibitor; the other set of mice -- induced to be diabetic -- were genetically unable to produce arginase-2. Both sets of mice showed no signs of kidney failure during the test period. The body naturally produces varieties of arginase. The liver produces arginase-1, while the kidneys produce arginase-2, which leads to kidney failure. The researchers did not detect arginase-1 in the kidneys of the mice, and they have not yet developed an arginase inhibitor that can differentiate between the two forms of the enzyme. "These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of diabetic nephropathy," the researchers report in the November 2011 issue of Diabetes. One of the symptoms of diabetic nephropathy is albuminuria -- losing protein in the urine.