Transition metal ions and metal-dependent enzymes

Transition metal ions, such as iron, copper, zinc, and manganese, along with the enzymes that depend on them (metalloenzymes), are essential components of nearly half of all known protein structures [2, 9]. These metals function as critical catalytic centers, structural stabilizers like zinc fingers, and redox-active sites for processes such as oxygen transport and electron transfer [4, 6]. Dysregulation of transition metal homeostasis, or metal dyshomeostasis, is implicated in a wide range of diseases, including genetic disorders of metal metabolism (e.g., Wilson's disease), neurodegenerative diseases like Alzheimer's, and various forms of cancer [1, 3]. Therapeutic strategies targeting these systems include the use of chelating agents to remove excess or toxic metals and small-molecule inhibitors that coordinate with metal ions in the active sites of enzymes [2, 8]. For instance, ACE inhibitors and HDAC inhibitors exert their effects by binding to zinc ions within their respective target enzymes [1, 2]. However, the widespread biological requirement for these metals presents a significant challenge in drug development, as achieving high selectivity is necessary to prevent the depletion of essential metals and avoid systemic toxicity [6, 7]. Consequently, monitoring metal levels and enzyme activity through biomarkers like serum ferritin or ceruloplasmin serves as a vital component of managing therapies that affect transition metal pathways [12, 13].

Other names

MetalloenzymesMetalloproteinsMetal-binding proteinsTransition metal homeostasis components

Chelation of free metal ions, coordination to catalytic active site metal ions for enzyme inhibition, ionophoric redistribution of metals, and inhibition of metal transport proteins.