Fragile-histidine-triad proteins (Fhits) occur in all eukaryotes but their function is largely unknown. Human Fhit is presumed to function as a tumor suppressor. Previously, we demonstrated that Fhits catalyze hydrolysis of not only dinucleoside triphosphates but also natural adenosine 5′-phosphoramidate (NH2-pA) and adenosine 5′-phosphosulfate (SO4-pA) as well as synthetic adenosine 5′-phosphorofluoridate (F-pA). Here, we describe a Fhit-catalyzed displacement of the amino group of nucleoside 5′-phosphoramidates (NH2-pNs) or the sulfate moiety of nucleoside 5′-phosphosulfates (SO4-pNs) by fluoride anion. This results in transient accumulation of the corresponding nucleoside 5′-phosphorofluoridates (F-pNs). Substrate specificity and kinetic characterization of the fluorolytic reactions catalyzed by the human Fhit, and other examples of involvement of fluoride in the biochemistry of nucleotides are described. Among other HIT proteins, human Hint1 catalyzed fluorolysis of NH2-pA 20 times and human Hint2 40 times more slowly than human Fhit.
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