Systems of Zymogen Activation **

During the thirties, Northrop, Kunitz and their co-workers gave to the world a set of crystallized enzymes and zymogens.1. They also conveyed a set of corresponding ideas: that certain proteolytic enzymes are produced by the body in precursor form, that these precursors can be activated by slight proteolysis, and that this process is usually catalyzed by enzymes. Moreover, they delineated a system in which certain enzymes have the function of activating the precursors of other enzymes. In this classic system, the process is initiated when the enterokinase of the intestine begins to activate the trypsinogen of the pancreatic secretion. The resulting trypsin then activates more of the trypsinogen, as well as the other zymo-gens of the pancreatic secretion, chymotrypsinogen and procarboxypeptidase. Here, there are two activator-enzymes: enterokinase, (now also called enteropeptidase), and trypsin; and the first can activate the precursor of the second. Other systems might have more such factors, activatable in parallel or in series. How long such a series might be is suggested by recent theories of blood coagulation.`~' It now seems appropriate to state explicity what has long been assumed-that there are basic similarities in various systems that have the common feature of zymogen activation. This one aspect of formal resemblance invites attention to the biochemical amplification' which accrues when an enzyme hastens the production of another enzyme. It also brings into focus questions of common mechanisms, such as the splitting of certain peptide bonds. These questions, in turn, lead to consideration of how far substitutions between systems, or even shared pathways might be possible, at least experimentally, and perhaps spontaneously in health or disease. Some progress along these lines has already been made. When crystallized trypsin became available, Eagle and Harris showed that it could activate partially purified prothrombin.' The converse procedure , in which a clotting factor was tested on precursors from the pan-creas, was described in this Journal, in 1954, with negative results.7 This under the title, "Activation of crystallized proenzymes by factors of the blood clotting and fibrinolytic systems.