[www.ncbi.nlm.nih.gov]

Proteases likely arose at the earliest stages of protein evolution as simple destructive enzymes necessary for protein catabolism and the generation of amino acids in primitive organisms.

proteases regulate the fate, localization, and activity of many proteins, modulate protein-protein interactions, create new bioactive molecules, contribute to the processing of cellular information, and generate, transduce, and amplify molecular signals. As a direct result of these multiple actions, proteases influence DNA replication and transcription, cell proliferation and differentiation, tissue morphogenesis and remodeling, heat shock and unfolded protein responses, angiogenesis, neurogenesis, ovulation, fertilization, wound repair, stem cell mobilization, hemostasis, blood coagulation, inflammation, immunity, autophagy, senescence, necrosis, and apoptosis. Consistent with these essential roles of proteases in cell behavior and survival and death of all organisms, alterations in proteolytic systems underlie multiple pathological conditions such as cancer, neurodegenerative disorders, and inflammatory and cardiovascular diseases.

Proteases are the efficient executioners of a common chemical reaction: the hydrolysis of peptide bonds (16).

mice and rats contain more protease genes (644 and 629, respectively) compared with humans despite the fact that their genomes are smaller (19, 20).

many proteases link their catalytic domains to a variety of specialized functional modules or domains that provide substrate specificity, guide their cellular localization, modify their kinetic properties, and change their sensitivity to endogenous inhibitors. These non-catalytic domains include archetypal sorting signals that direct these enzymes to their proper location, autoinhibitory prodomains that prevent premature activation, and ancillary domains that facilitate homotypic interactions or heterotypic contacts with other proteins, substrates, receptors, or inhibitors. Some of these ancillary domains (like the epidermal growth factor domains) have been very successful in their incorporation into proteases and are present in a variety of enzymes from different families, whereas other domains (such as the thrombospondin repeats of ADAMTSs) have expanded within the same enzyme, forming long tandem repeats (29).