Interaction of protein C inhibitor with the type II transmembrane serine protease enteropeptidase.
The serine protease inhibitor protein C inhibitor (PCI) is expressed in many human tissues and exhibits broad protease reactivity. PCI binds glycosaminoglycans and certain phospholipids, which modulate its inhibitory activity. Enteropeptidase (EP) is a type II transmembrane serine protease mainly found on the brush border membrane of epithelial cells in the duodenum, where it activates trypsinogen to initiate the digestion of food proteins. Some active EP is also present in duodenal fluid and has been made responsible for causing pancreatitis in case of duodeno-pancreatic reflux. Together with its substrate trypsinogen, EP is furthermore present in the epidermis and in some cancer cells. In this report, we show that PCI inhibited EP with an apparent 2nd order rate constant of 4.48 × 10(4) M(-1) s(-1). Low molecular weight (LMWH) and unfractionated heparin (UFH) slightly reduced the inhibitory effect of PCI. The SI (stoichiometry of inhibition) value for the inhibition of EP by PCI was 10.8 in the absence and 17.9 in the presence of UFH (10 U/ml). By inhibiting trypsin, chymotrypsin, and additionally EP, PCI might play a role in the protection of the pancreas from autodigestion. Furthermore the interaction of PCI with EP may influence the regulation of epithelial differentiation.
Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Thomas A
TA
Prohaska
Felix C
FC
Wahlmüller
Margareta
M
Furtmüller
Margarethe
M
Geiger
D000818:Animals; D000991:Antithrombins / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004765:Enteropeptidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011485:Protein Binding; D018046:Protein C Inhibitor / Q000378:metabolism* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D015843:Serpins / Q000378:metabolism / Q000494:pharmacology
D000991:Antithrombins; D018046:Protein C Inhibitor; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D006493:Heparin; D004765:Enteropeptidase