Zinc transporters and zinc-dependent enzymes

Zinc transporters and zinc-dependent enzymes constitute a vast and essential group of proteins that regulate zinc homeostasis and utilize zinc as a critical cofactor for structural and catalytic functions (PubMed: 34624823). Zinc transporters, primarily from the SLC30 (ZnT) and SLC39 (ZIP) families, manage the influx, efflux, and compartmentalization of zinc ions, which act as secondary messengers in signaling pathways (PMC: 12827705). Zinc-dependent enzymes, including carbonic anhydrases, matrix metalloproteinases (MMPs), and histone deacetylases (HDACs), are involved in diverse processes such as pH regulation, extracellular matrix remodeling, and epigenetic modification (PMC: 7247254). Dysregulation of these proteins is implicated in numerous diseases, including cancer, where ZIP transporters often promote proliferation, and diabetes, which is linked to ZnT8 function (PMC: 4350120). Therapeutic strategies targeting this group include small-molecule inhibitors that coordinate with the catalytic zinc ion and emerging biologics like antibody-drug conjugates targeting specific transporters (Front. Immunol. 2026). While many drugs in this class are clinically successful, such as ACE inhibitors and HDAC inhibitors, the high conservation of zinc-binding motifs presents significant challenges for achieving selectivity and avoiding off-target toxicity (Front. Chem. 2022).

Other names

Zinc-binding proteinsZinc metalloproteinsZinc homeostasis proteinsZinc-dependent metalloenzymes

Drugs targeting this group primarily function through the inhibition of the catalytic zinc-binding site using zinc-binding groups (ZBGs) such as hydroxamates, sulfonamides, or carboxylates, which coordinate with the zinc ion to block substrate access. Other mechanisms include the use of antibody-drug conjugates (ADCs) to target specific zinc transporters overexpressed in tumors and the modulation of zinc homeostasis to disrupt signaling pathways.