Metalation and activation of Zn enzymes via early secretory pathway-resident ZNT proteins.

Zinc (Zn), an essential trace element, binds to various proteins, including enzymes, transcription factors, channels, and signaling molecules and their receptors, to regulate their activities in a wide range of physiological functions. Zn proteome analyses have indicated that approximately 10% of the proteins encoded by the human genome have potential Zn binding sites. Zn binding to the functional site of a protein (for enzymes, the active site) is termed Zn metalation. In eukaryotic cells, approximately one-third of proteins are targeted to the endoplasmic reticulum; therefore, a considerable number of proteins mature by Zn metalation in the early secretory pathway compartments. Failure to capture Zn in these compartments results in not only the inactivation of enzymes (-Zn enzymes), but also their elimination via degradation. This process deserves attention because many Zn enzymes that mature during the secretory process are associated with disease pathogenesis. However, how Zn is mobilized via Zn transporters, particularly ZNTs, and incorporated in enzymes has not been fully elucidated from the cellular perspective and much less from the biophysical perspective. This review focuses on Zn enzymes that are activated by Zn metalation via Zn transporters during the secretory process. Further, we describe the importance of Zn metalation from the physiopathological perspective, helping to reveal the importance of understanding Zn enzymes from a biophysical perspective.