Mammalian metal-dependent enzymes

Mammalian metal-dependent enzymes, or metalloenzymes, are a diverse group of proteins that require metal ion cofactors, such as zinc, iron, or magnesium, to perform their catalytic functions (Andreini et al., 2008). These enzymes are ubiquitous in mammalian physiology, participating in essential processes including DNA replication, protein degradation, and cellular signaling (Chen et al., 2019). The metal ion typically resides in the active site, where it facilitates catalysis by acting as a Lewis acid or participating in redox transformations (Solomon et al., 1996). Dysregulation of various metalloenzymes is implicated in a wide range of diseases, such as cancer, cardiovascular disorders, and neurodegeneration (Iqbal, 2021). Consequently, they are major targets for drug development, with many approved therapies acting as inhibitors that bind directly to the catalytic metal (Liao et al., 2016). For example, ACE inhibitors are used for hypertension, while HDAC inhibitors are employed in oncology (Chen et al., 2019). A primary challenge in targeting these enzymes is achieving selectivity, as many different metalloenzymes share similar metal-coordination geometries (Riccardi et al., 2018). This lack of specificity can lead to significant safety concerns, such as the musculoskeletal toxicity observed with early matrix metalloproteinase inhibitors (Chen et al., 2019).

Other names

MetalloenzymesMetal-dependent enzymesMammalian metalloproteinsMMEs

Inhibition of enzymatic activity through the coordination of a metal-binding group (MBG) to the catalytic metal ion (e.g., Zn2+, Fe2+, Mg2+) in the active site, which prevents substrate binding and disrupts the catalytic cycle (Chen et al., 2019; Liao et al., 2016).