metallopeptidases

Metallopeptidases are proteolytic enzymes that require a metal ion in their active site to hydrolyze peptide bonds. The most common metal is zinc, though some members use other divalent metals. Catalysis depends on metal-coordinating residues, typically histidines, and a third ligand such as a glutamate that helps activate a bound water molecule for nucleophilic attack on the substrate. Many metallopeptidases contain a conserved motif around the metal-binding site, exemplified by HEXXH, with additional residues contributing to catalysis and substrate recognition.

Metallopeptidases comprise several subfamilies, including matrix metalloproteinases (MMPs), adamalysins (ADAMs and ADAMTSs), astacins, and members of the neprilysin family, among others. They are found as secreted enzymes in the extracellular space, membrane-anchored proteins, or intracellular proteases within organelles. Their substrates include extracellular matrix components such as collagens and proteoglycans, signaling peptides, and pro-forms of cytokines and growth factors. By cleaving specific substrates, they regulate tissue remodeling, development, wound healing, angiogenesis, and inflammation.

Regulation occurs at transcription, zymogen activation, localization, and inhibition by endogenous inhibitors such as tissue inhibitors of metalloproteinases (TIMPs).

Pathology and therapeutics: excessive or misregulated metallopeptidase activity is linked to cancer invasion and metastasis, arthritis, fibrosis, and neurodegenerative diseases. TIMPs and synthetic inhibitors have been developed to modulate activity, but clinical success has been limited by issues of specificity and adverse effects.