Abstract
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.
Highlights
Zinc deficiency causes myriad pathophysiological symptoms, but why distinct phenotypes are generated by zinc deficiency remains unclear
The alkaline phosphatase (ALP)-family proteins are the only ectonucleotidases that contribute to all reactions in the hydrolysis of extracellular ATP to adenosine through ADP and AMP17
The activity of endogenous Tnap substantially decreased (>95%) in zinc-deficient cultures, whereas ENTPD1/CD39 and prostatic acid phosphatase (PAP) activities were almost unchanged (Fig. 2a–d), which is consistent with their recognized features; ENTPD1/CD39 contains calcium or magnesium, instead of zinc in the active site[34,38], and PAP has been characterized as a histidine phosphatase[35]
Summary
Zinc deficiency causes myriad pathophysiological symptoms, but why distinct phenotypes are generated by zinc deficiency remains unclear. Iron deficiency mainly results in anemia due to the higher iron content in red blood cells Addressing this critical question regarding zinc deficiency can potentially lead to novel therapeutic applications of zinc to improve human health. Recent crystal structural studies revealed that the ENPP proteins and NT5E/CD73 contain two zinc ions in their active sites[26,27,28,29,30,31], as in ALP proteins[32,33], whereas ENTPD1/CD39 and PAP do not harbor zinc at the active sites[34,35] This raises the possibility that zinc status is associated with extracellular adeninenucleotide metabolism, and with purinergic signaling. We test this hypothesis by directly measuring the activities of these ectoenzymes in cultured cells (both cells endogenously expressing the enzymes and cells overexpressing the enzymes) and in rats that were fed zinc-deficient diets
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