metalloproteinases

Metalloproteinases are a family of zinc-dependent proteases that cleave peptide bonds in proteins, with a prominent role in remodeling the extracellular matrix. They rely on a catalytic zinc ion at the active site and share a conserved motif, HExGHXXGXXH, in which three histidines coordinate the zinc and a downstream glutamate acts as a general base in catalysis.

The family includes several groups. Matrix metalloproteinases (MMPs) are secreted or membrane-type enzymes that degrade various extracellular matrix components such as collagens, gelatin, and laminin, thereby enabling tissue remodeling. ADAMs (a disintegrin and metalloproteinase) are mainly membrane-anchored enzymes involved in ectodomain shedding of cell-surface proteins. ADAMTS (ADAMs with thrombospondin motifs) are secreted, ECM-associated proteases with thrombospondin repeats.

Activity is tightly regulated at multiple levels. Most metalloproteinases are synthesized as inactive proenzymes and require proteolytic removal of a prodomain to become active. Regulation also occurs through transcriptional control and through endogenous inhibitors, particularly the tissue inhibitors of metalloproteinases (TIMPs), which bind active enzymes to limit proteolysis.

Physiological roles include normal development, tissue remodeling, wound healing, and angiogenesis. Dysregulation of metalloproteinases is implicated in pathology, notably cancer invasion and metastasis, inflammatory and degenerative diseases such as arthritis, fibrosis, and cardiovascular disorders.

Therapeutically, broad-spectrum metalloproteinase inhibitors have faced challenges due to toxicity and limited specificity. Current efforts focus on selective inhibition of individual MMPs, or targeting specific ADAM/ADAMTS activities and their regulatory pathways, with relevance to oncology, fibrosis, and inflammatory diseases.