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Newly discovered cell mechanism uses amplified nitric oxide to fight C. diff
Date:8/21/2011

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In addition to Dr. Stamler, investigators from the University of Texas in Galveston, the University of California, Tufts University and the Commonwealth Medical College collaborated on the research. The University of Texas researchers first determined that NO helped protect cells against C. diff and approached Dr. Stamler to determine if SNO was also involved.

C. diff is the most common cause of hospital-acquired infectious diarrhea and life-threatening inflammation of the colon. It originates when normal, competing bacteria in the gastrointestinal tract are wiped out by the use of antibiotics. This allows C. diff bacteria to grow out of control.

The C. diff bacteria secrete a toxin that cleaves or cuts itself to generate a fragment that can penetrate cells, damaging them and resulting in a hemorrhagic injury to the gastrointestinal tract. The toxin is activated when inositolhexakisphosphate (InsP6), a substance prevalent in leafy vegetables and the gastrointestinal tract, binds to it, enabling the toxin to change shape and cleave itself.

The research shows that upon activation, GSNO, a NO donor molecule, binds to the toxin and nitrosylates it. This can only occur when InsP6 binds to the toxin.

The change in shape that results when InsP6 binds to the toxin is what enables the GSNO to target and inactivate the toxin by directly binding to the active site. There, the GSNO can nitrosylate (SNO) the cysteine to inactivate the toxin. These findings are especially significant as they suggest that GSNO has evolved to recognize shape changes in the toxins it targets.

Prior to this, researchers knew GSNO could produce SNO in many classes of proteins but there was little to no precedent for it binding to toxins or explaining how this SNO modification protects against infectious agents, Dr. Stamler says.

"The new research suggests GSNO, and S-nitrosylation, more generally, may have a unive
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Contact: Kevin Mayhood
kevin.mayhood@case.edu
216-368-4442
Case Western Reserve University
Source:Eurekalert

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