The Arcana of Zinc

Abstract

This perspective discusses the essential micronutrient zinc, which functions in >3000 human proteins (the zinc proteome), and the implications of three aspects to ascertain an adequate zinc status for human health. First, the advent of highly sensitive fluorescent (bio)chemicals revealed cellular pools of zinc ions involved in signaling and secretion from cells for paracrine, autocrine, and possibly endocrine functions. Zinc signaling adds a yet unaccounted number of targeted proteins to the already impressive number of zinc proteins. Second, cellular zinc concentrations are remarkably high in the order of the concentrations of major metabolites and, therefore, at the cellular level zinc is not a trace element. Zinc is also not an antioxidant because zinc ions are redox-inactive in biology. However, zinc can express indirect pro-oxidant or proantioxidant effects depending on how cellular zinc is buffered. Zinc sites in proteins and other biomolecules can become redox-active when zinc is bound to the redox-active sulfur donor atom of cysteine. This interaction links zinc and redox metabolism, confers mobility on tightly bound zinc, and has implications for treating zinc deficiency. Third, the concept of zinc deficiency in blood as the only measure of an inadequate zinc status needs to be extended to zinc dyshomeostasis in cells because overwhelming the mechanisms controlling cellular zinc homeostasis can result in either not enough or too much available zinc. We need additional biomarkers of zinc status that determine cell-specific changes and perturbations of the system regulating cellular zinc, including functional deficits, and address the multiple genetic and environmental factors that can cause a conditioned zinc deficiency or overload. Considering the wider context of altered zinc availability in different organs, cells, and organelles impinges on whether zinc supplementation will be efficacious and adds another dimension to the already high health burden of zinc deficiency and its sequelae worldwide.

Keywords: Zinc; biomarkers; metallostasis; micronutrients; zinc proteome.

FIGURE 1

Zinc signatures in proteins. (A). Prediction of zinc sites in proteins. Zinc-binding sites of zinc proteins with known zinc ligands (L)—usually 3 for catalytic zinc sites and 4 for structural zinc sites from the side chains of histidine, cysteine, glutamate, or aspartate—can be used to search for analogous sites in proteins for which zinc-binding sites have not been established. The number of amino acids (X) between the ligands can vary (a-f). (B). Zinc binding at protein interfaces mediating protein-protein interactions. One or two zinc-binding ligands in a protein do not give sufficient information for a predictive signature. Nevertheless, zinc binding can occur when additional ligands stem from a different protein.