Proteases free in the internal milieu are capable of considerable mischief. These may be proteases of endogenous origin from the clotting or immune systems or they may be exogenous proteases introduced by invading parasites. To regulate proteases, animals and plants have evolved a variety of protease inhibitors, mostly proteins, that are of two fundamental categories, the active-site inhibitors and inhibitors of the α₂-macroglobulin class. The active site inhibitors bind directly to the active site of the target protease whereas the α₂-macroglobulins bind the protease by enfolding it in the coils of the polypeptide chain of α₂-macroglobulin and, in some cases, by establishing isopeptide bonds with ε-amino groups of lysine residues of the target protease. This leaves free the active site of the α₂-macroglobulin-bound protease. The principal function of α₂-macroglobulin is to convey the bound protease molecule to cell-surface receptors that recognize specifically the protease-reacted form of α₂-macroglobulin. The molecule of α₂-macroglobulin, with its cargo of protease, is then internalized and degraded in secondary lysosomes. In contrast to the active-site inhibitors, which typically are relatively fastidious, binding only to a subset of all proteases, the α₂-macroglobulins typically bind proteases of all different enzymatic mechanisms, and thus are ideally suited to bind and clear proteases originating from foreign cells, such as the cells of invading parasites.