Physiological metalloproteins and metalloenzymes

Physiological metalloproteins and metalloenzymes are a vast and diverse class of proteins that incorporate metal ions as essential cofactors for their structural integrity and biological activity [2, 4]. These proteins utilize metals such as iron, zinc, copper, magnesium, and manganese to perform critical functions including oxygen transport (e.g., hemoglobin), electron transfer (e.g., cytochromes), and catalysis of complex biochemical reactions (e.g., carbonic anhydrase and matrix metalloproteinases) [1, 3, 5]. In disease, dysregulation of these proteins or the underlying metal homeostasis is linked to conditions ranging from cancer and inflammation to neurodegenerative and cardiovascular diseases [4, 8]. Therapeutic strategies often involve small molecules with metal-binding pharmacophores designed to inhibit specific metalloenzymes by coordinating with the active-site metal ion [8]. However, achieving selectivity remains a significant challenge due to the structural similarities among different metal-binding sites, leading to potential off-target effects and toxicity [6, 8].

Other names

MetalloproteinsMetalloenzymesMetal-binding proteinsMetalloproteome

Drugs targeting this class typically utilize metal-binding pharmacophores to coordinate with the active-site metal ion, inhibiting catalytic activity or blocking substrate binding [8]. Mechanisms also include competitive inhibition and modulation of metal ion coordination geometry [6].