A possible zymogen self-destruct mechanism preventing pancreatic autodigestion.
Incubation at 37 degrees C of human cationic trypsinogen purified by PAGE electrophoresis, results in development of proteolytic activity (enzyme Y) capable of rapidly degrading cationic and anionic trypsinogens to inert products. Enzyme Y appears to be a serine protease with a molecular weight of about 20,000 daltons and is different from any of the known pancreatic enzymes. The active enzyme may be derived from trypsinogen itself or a hitherto unrecognized precursor contaminating the trypsinogen fraction used in this work. Appearance of enzyme Y activity seems to be associated with the presence of traces of free trypsin. Enzyme Y possesses insignificant or no activity when tested with a variety of synthetic trypsin, chymotrypsin and other protease substrates. It is not inactivated by the specific trypsin and chymotrypsin inhibitors TLCK and TPCK, but its activity is reduced gradually by increasing concentrations of pancreatic secretory trypsin inhibitor. Ca2+ concentrations greater than 3 mM strongly inhibit enzyme Y, and diisopropylfluorophosphate completely inactivates it. The enzyme is stable when incubated at pH 1.9 and 37 degrees C for 30 min and its activity is not abolished by treatment with Hg2+. When added to pancreatic juice with low inhibitor content it causes rapid inactivation of zymogens without significant release of active enzymes or reduction of pancreatic trypsin inhibitor. Its physiological role may be perceived as a second line of defense against premature intrapancreatic activation of zymogens. Enzyme Y activity may be generated when trypsin inhibitor, the first line of defense, is sufficiently depleted by complex formation with inappropriately released trypsin to permit dissociation of a small amount of trypsin from this complex. This in turn may lead to activation of enzyme Y and inactivation of the zymogens of pancreatic proteases.
Rinderknecht
H
H
Veterans Administration Medical Center, Sepulveda, CA.
Adham
N F
NF
Renner
I G
IG
Carmack
C
C
D001329:Autolysis / Q000517:prevention & control*; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors*; D006801:Humans; D007531:Isoflurophate / Q000494:pharmacology; D008970:Molecular Weight; D010179:Pancreas / Q000201:enzymology*; D010189:Pancreatic Juice / Q000201:enzymology; D012697:Serine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism*; D014362:Trypsinogen / Q000037:antagonists & inhibitors
D004792:Enzyme Precursors; D007531:Isoflurophate; D014362:Trypsinogen; D012697:Serine Endopeptidases