NITRIC OXIDE INHIBITION OF TARGET ENZYMES

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Nitric oxide (NO) is a diatomic radical which can diffuse readily across biological membranes. NO controls and influences a number of critical physiological processes. The best characterized examples of physiological responses controlled by NO include vasodilation and regulation of normal vascular tone, inhibition of platelet aggregation, neuronal transmission and cytostasis. One proposed cellular target for NO which could mediate such cytostatic effects is ribonucleotide reductase (RNR). NO would also be expected to influence related proteins such thioredoxin and thioredoxin reductase. Inhibition of these proteins would also be expected to induce cytostasis. The inhibition of DNA synthesis in target cells has been reported, however, the mechanism of the inhibition is unknown. The goal of the proposed studies, therefore, is to determine the molecular' mechanism of NO inhibition of E. coli ribonucleotide reductase (RNR) and the effect on NO on related proteins. The studies will use cloned and expressed sources of the proteins to address the following specific aims: (l) the effect of NO on thioredoxin (Trx) and thioredoxin reductase (TR), (2) the effect of NO on enzymatic turnover of RNR, (3) the effect of NO on the assembly of the iron center of RNR.