Zinc deficiency causes myriad pathophysiological symptoms, but why distinct phenotypes are generated by zinc deficiency remains unclear. Considering that several ectoenzymes involved in purinergic signaling through extracellular adenine-nucleotide hydrolysis possess zinc ions in their active sites, and disorders in purinergic signaling result in diverse diseases that are frequently similar to those caused by zinc deficiency, herein we examine whether zinc deficiency affects extracellular adenine-nucleotide metabolism. Zinc deficiency severely impairs the activities of major ectoenzymes (ENPP1, ENPP3, NT5E/CD73, and TNAP), and also strongly suppresses adenine-nucleotide hydrolysis in cell-membrane preparations or rat plasma, thereby increasing ATP and ADP levels and decreasing adenosine levels. Thus, zinc deficiency delays both extracellular ATP clearance and adenosine generation, and zinc modulates extracellular adenine-nucleotide metabolism. Since the finely tuned balance between extracellular adenine nucleotides and adenosine is critical for purinergic signaling, these findings provide a novel insight into why zinc deficiency results in diverse symptoms.
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