60,61 Rinderknecht

initially alleged that mesotrypsin can degrade trypsinogens, but later he withdrew this claim and attributed the trypsinogen-degrading activity to enzyme Y.60 Rinderknecht believed that enzyme Y was probably a degradation fragment of cationic trypsin,61 perhaps complexed with pancreatic secretory trypsin inhibitor,62 although he acknowledged the possibility of contamination with an unknown protease.61 Our findings indicated that CTRC is in fact enzyme Y, and following Rinderknecht’s theory, CTRC protects the pancreas by decreasing trypsinogen concentrations during inappropriate zymogen activation (Fig. 1). CTRC-mediated trypsinogen degradation is more likely to play a protective role against pancreatitis than CTRC-mediated trypsin inactivation, because the former reaction is much faster, Acalabrutinib molecular weight and trypsinogen concentrations are much higher. When trypsinogen autoactivation is measured in the presence of CTRC, the ultimate trypsin levels generated are lower and depend on the trypsinogen/CTRC ratio and the calcium concentration. Thus, in essence, CTRC regulates Pritelivir trypsinogen autoactivation through degradation. The cationic trypsinogen mutation p.R122H, which causes hereditary chronic pancreatitis,13 eliminates the Arg122 autolytic cleavage site,

and thereby blocks CTRC-mediated trypsin and trypsinogen degradation. Autoactivation of p.R122H mutant trypsinogen in the presence of CTRC results in higher

trypsin levels than those observed with wild-type cationic trypsinogen, suggesting that mutation p.R122H exerts its pathogenic effect by interfering with the CTRC-dependent defense mechanism of trypsinogen degradation. Human digestive carboxypeptidases CPA1, CPA2, and CPB1 are secreted by the pancreas as inactive proenzymes containing a 94–96 amino-acid-long propeptide.63 Activation of procarboxypeptidases is initiated by proteolytic cleavage at the C-terminal end of the propeptide by trypsin. The trypsin-cleaved propeptide is still inhibitory, suppressing approximately 90% of carboxypeptidase activity. Recently, we demonstrated that CTRC induces nearly a 10-fold increase in the activity of trypsin-activated CPA1 and CPA2.64 CTRC exerts its effect by proteolyzing the α-helical connecting segment of the propeptide, which 上海皓元 becomes accessible only after tryptic activation. As a result, the propeptide dissociates and becomes completely degraded, resulting in full carboxypeptidase activity. CTRC cleaves the connecting segment in the propeptide at multiple sites, but the critical cleavage appears to be at the conserved Leu96–Leu97 peptide bond. Other human pancreatic chymotrypsins (CTRB1, CTRB2, CTRL1) or elastases (ELA2A, ELA3A, ELA3B) are inactive or markedly less effective at promoting procarboxypeptidase activation. Taken together, these observations indicate that CTRC is an essential co-activator of proCPA1 and proCPA2.