Metalation and activation of Zn²⁺enzymes via early secretory pathway-resident ZNT proteins

Abstract

Zinc (Zn²⁺), 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. Zn²⁺ proteome analyses have indicated that approximately 10% of the proteins encoded by the human genome have potential Zn²⁺ binding sites. Zn²⁺binding to the functional site of a protein (for enzymes, the active site) is termed Zn²⁺metalation. In eukaryotic cells, approximately one-third of proteins are targeted to the endoplasmic reticulum; therefore, a considerable number of proteins mature by Zn²⁺metalation in the early secretory pathway compartments. Failure to capture Zn²⁺ in these compartments results in not only the inactivation of enzymes (apo-Zn²⁺ enzymes), but also their elimination via degradation. This process deserves attention because many Zn²⁺ enzymes that mature during the secretory process are associated with disease pathogenesis. However, how Zn²⁺is mobilized via Zn²⁺ 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 Zn²⁺ enzymes that are activated by Zn²⁺ metalation via Zn²⁺ transporters during the secretory process. Further, we describe the importance of Zn²⁺ metalation from the physiopathological perspective, helping to reveal the importance of understanding Zn²⁺ enzymes from a biophysical perspective.