Nitric oxide is generated in the metabolism of arginine and serves as a messenger in signal transduction systems. Upon reaction with superoxide anion, nitric oxide is converted to the highly toxic peroxynitrite derivative. The reaction of peroxynitrite with tyrosine residues of proteins leads to stable nitrotyrosine derivatives. Because nitrotyrosine derivatives cannot undergo covalent modification by the enzyme-catalyzed phosphorylation or adenylylation of their hydroxyl groups, the nitration of tyrosine residues in regulatory proteins could interfere with cellular regulation of diverse pathways by signal transduction mechanisms. To determine the effect of nitration on a regulatory enzyme we studied the nitration of Escherichia coli glutamine synthetase whose activity is under strict control by a mechanism involving the cyclic adenylylation and deadenylylation of a specific tyrosine residue. Nitration of the unadenylylated (active) form of glutamine synthetase by reaction with peroxynitrite led to its conversion to a form exhibiting characteristics of the adenylylated enzyme with respect to stability of subunit interactions, sensitivity to allosteric control of feedback inhibitors, pH optimum, and divalent cation specificity. Nitration of the adenylylated enzyme led to complete loss of catalytic function. These results demonstrate that the nitration of regulatory enzymes by peroxynitrite produced from nitric oxide, under conditions of """"""""oxidative stress"""""""" can lead to a loss in ability of the cell to regulate key enzyme activities by the cyclic interconversion of tyrosine residues between modified and unmodified forms.
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