Proteolytic enzymes, past and present

William Beaumont's pioneering research on gastric secretion has been germinal in the discovery of proteolytic enzymes and the elucidation of their chemical structure, physiological roles, and biochemical evolution. Although the mammalian digestive enzymes, notably those of gastric and pancreatic origin, have been among the best characterized, of even greater interest and complexity are those that fulfill regulatory functions by limiting their action on specific peptide bonds in target protein substrates. The difference between digestive and regulatory proteases can best be understood by considering their evolutionary relationships on the basis of the organization of both their genes and the proteins themselves. An analysis of representative members of protease families, notably the mammalian serine proteases, suggests that they are the products of processes of recombination of gene segments that give rise to functionally and structurally distinct domains. The evolutionary variability introduced by combinations of domains appears to be far more restricted than if each protein molecule were the product of a single and unique evolutionary event.