metzincins

Metzincins are a superfamily of zinc-dependent metalloproteases that share a conserved catalytic mechanism and structural features. The active site coordinates a catalytic zinc ion using histidine residues, with a catalytic glutamate acting as a general base, and a conserved methionine-containing Met-turn that helps shape the active site. This combination of features places metzincins in a distinct group within metalloproteases.

The metzincin superfamily encompasses several major families, including the matrix metalloproteinases (MMPs), the adamalysins (ADAMs and ADAMTSs), the astacins (which include the tolloid/BMP1-like proteases and meprins), and related enzymes. Members often differ in domain organization: MMPs typically have catalytic domains and hemopexin-like domains; ADAMs possess disintegrin and cysteine-rich regions and, in many cases, a transmembrane segment; ADAMTS enzymes are secreted and carry thrombospondin motifs; astacins show varying auxiliary domains that influence localization and substrate recognition.

Functionally, metzincins participate in extracellular matrix remodeling, processing of cytokines and growth factors, and activation or inactivation of various signaling molecules. They are involved in development, wound healing, angiogenesis, and tissue repair, as well as in disease processes such as cancer invasion, arthritis, fibrosis, and cardiovascular remodeling. Activation of these enzymes usually occurs by proteolytic removal of their inhibitory propeptide, and their activity is tightly regulated at transcriptional, translational, and post-translational levels. Inhibition is commonly achieved by tissue inhibitors of metalloproteinases (TIMPs), along with other regulatory mechanisms that control localization and substrate accessibility.

Overall, metzincins form a diverse and evolutionarily conserved group of proteases essential for controlled proteolysis in physiology and disease.