Metalloproteases

Metalloproteases are a broad class of proteolytic enzymes that require a metal ion, typically zinc, in their catalytic site to hydrolyze peptide bonds. They participate in the regulated remodeling of proteins and peptides in tissues, as well as processing various signaling molecules.

Most metalloproteases belong to the metzincin superfamily, characterized by a zinc-binding motif in the catalytic domain, commonly HEXXHXXGXXH. The largest and best-studied subgroup includes matrix metalloproteinases (MMPs), which are secreted or membrane-associated enzymes that degrade extracellular matrix components. Other significant families include ADAMs (a disintegrin and metalloproteinases) and ADAMTS (ADAMTS proteases), which can shed cell-surface proteins or modify extracellular matrix. Some bacterial proteases and other distant families also fall under metalloproteases.

Enzymes of this class are typically synthesized as inactive zymogens (proenzymes) and require activation through removal of an N-terminal propeptide containing a cysteine switch that disrupts the active site. Activity is tightly regulated by endogenous inhibitors, notably tissue inhibitors of metalloproteinases (TIMPs), which bind to the catalytic site and block proteolysis.

The catalytic mechanism involves coordination of zinc by three histidine residues in the active site and a catalytic glutamate, which activates a bound water molecule to attack the peptide bond. This enables broad substrate versatility, including collagen and elastin in the extracellular matrix, processing of cytokines and growth factors, and shedding of membrane-bound receptors.

Physiological roles include development, tissue remodeling, wound healing, angiogenesis, and immune responses. Dysregulation is linked to diseases such as cancer invasion and metastasis, arthritis, fibrosis, and neurodegenerative conditions. Therapeutic targeting faces challenges due to overlap among family members and adverse effects from broad inhibition.