Metalloproteases are the most diverse of the four main protease types, with more than 50 families classified to date. Most metalloproteases require zinc, but some use cobalt, which activates the water molecule. The metal ion is coordinated to the protein by amino acid ligands. The known metal ligands are His, Glu, Asp or Lys. The majority of these proteases are endopeptidases in comparison to the aminopeptidases. MMPs, ADAMs and ADAMTSs are regulated by TIMPs, which have different specificity toward different members of these families.
Metalloproteases are important in many aspects of biology, ranging from cell proliferation, differentiation and remodeling of the extracellular matrix (ECM) to vascularization and cell migration. These events occur several times during organogenesis in both normal development and during tumor progression. Mechanisms of metalloprotease action underlying these events include the proteolytic cleavage of growth factors so that they can become available to cells not in direct physical contact, degradation of the ECM so that founder cells can move across tissues into nearby stroma, and regulated receptor cleavage to terminate migratory signaling. Most of these processes require a delicate balance between the functions of matrix metalloproteases (MMPs) or metalloprotease-disintegrins (ADAMs) and natural tissue inhibitors of metalloproteases (TIMPs).