Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.9 (enterokinase)
675 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rats fed control and ethanol-containing Lieber-DeCarli diets for a period of 12 months, the bile did not contain any enterokinase, the pancreatic juice did not contain any plasmin or thrombin, but in animals fed high fat diet with ethanol, trypsinogen and chymotrypsinogen were significantly increased and trypsin inhibitor decreased. In the tissue, free trypsin and cathepsin B were increased. Composite profile of trypsinogen in gel segments obtained from the pancreatic juice and the tissue showed higher peaks of cationic and anionic variants of trypsinogen in animals fed ethanol. There was no evidence of mesotrypsinogen or of enzyme Y in the juice or the tissue. These studies show that serine proteases and cathepsin B may play a major role in the pathobiology of alcoholic pancreatitis.
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PMID:Effect of chronic ethanol feeding on factors leading to inappropriate intrapancreatic activation of zymogens in the rat pancreas. 128 69

Activation of trypsinogen is thought to trigger the autodigestive process in acute pancreatitis. The lysosomal enzyme cathepsin B was suggested to cause the activation of trypsinogen because it is known that cathepsin B is able to activate trypsinogen in special circumstances and that lysosomal and digestive enzymes are colocalized within intracellular vacuoles in the early stage of pancreatitis. As yet this hypothesis has been difficult to prove because activated trypsin is difficult to quantify in pancreatitis by conventional enzymatic measurements. We therefore employed an ELISA for trypsin activating peptide (TAP), which is a small peptide cleaved during the activation of trypsinogen and can be determined reliably. Supraphysiological concentrations of cerulein (1 nM-1 microM) resulted in a marked increase in TAP in freshly isolated pancreatic acinar cells, indicating activation of trypsinogen. This activation as determined by the TAP increase was significantly reduced by the serine protease inhibitor Fut-175 but not by the cathepsin B inhibitors E-64 and NCO-700. The concentrations of NCO-700 and E-64 abolished the cathepsin B activity of pancreatic acinar cells but did not significantly reduce the trypsin activity (after enterokinase preincubation); correspondingly the concentrations of Fut-175 used abolished the trypsin activity but did not reduce the cathepsin B activity. The results indicate that an autoactivation of trypsin rather than an activation of trypsinogen by cathepsin B triggers trypsin activation by supramaximal cerulein concentrations.
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PMID:Inhibition of cathepsin B does not affect the intracellular activation of trypsinogen by cerulein hyperstimulation in isolated rat pancreatic acinar cells. 943 69

In healthy subjects, the 3 known pancreatic trypsinogens, which are endopeptidases belonging to the chymotrypsin superfamily, are activated by enterokinase and partial autoactivation in the duodenum. The premature activation of trypsinogen in the pancreatic interstitium, with the subsequent activation of other pancreatic zymogens, is believed to lead to the autodigestion of the gland, this being the first event in acute pancreatitis. The mechanisms that lead to trypsinogen, activation in acute pancreatitis are largely unknown. However, ischemia, hypercalcemia and the activation of cathepsin B (by cholecystokinin) are thought to be of importance. The easiest and most reliable way to assess trypsinogen activation is the measurement of the activation peptide, TAP, in urine, plasma, pancreatic tissue or ascitic fluid. In the animal model of acute pancreatitis, TAP in ascites and pancreatic tissue has been shown to correlate with the presence and extent of necroses. It has proven to be a good marker for the severity of pancreatitis and is a useful marker in examining the pathophysiology and possible treatment modalities in the animal model of acute pancreatitis. Studies on TAP in human acute pancreatitis were most commonly focused on urinary TAP. Within a 48-hour time frame after the onset of the disease, TAP was a good predictor of the severity of acute pancreatitis. The main advantage over other markers, such as CRP, is that TAP is the earliest marker of necrosis to be increased. Also, increased levels of TAP in ascitic fluid were shown to correlate well with pancreatic necroses. In our experience, plasma TAP was found to have a "diagnostic window" within the first 3 days predicting pancreatic necroses. Positive TAP gave a very good positive prediction and a high specificity towards the development of pancreatic necroses, but did not differ between necrotizing pancreatitis with systemic complications or uncomplicated necrotizing pancreatitis. We therefore think that plasma TAP is a very good marker for local complication in acute pancreatitis and its routine measurements may help to identify patients at a high risk within the first days of the disease.
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PMID:Mechanism and role of trypsinogen activation in acute pancreatitis. 1057 41

Autodigestion by proteolytic enzymes is thought to represent the critical mechanism by which acute pancreatitis is initiated. Where and why pancreatic proteases, which are physiologically stored and secreted as inactive precursor zymogens, are activated within the pancreas has remained controversial. Here we present data which indicate that: the lysosomal protease cathepsin B can activate trypsinogen in vitro in a manner that is similar to trypsinogen activation by enterokinase; that cathepsin B colocalizes with trypsinogen in the secretory compartment of the rat pancreas and of the human pancreas; that trypsinogen activation begins in a secretory compartment that is distinct from mature zymogen granules; and that the inhibition of cathepsin B can either increase or decrease premature trypsinogen activation depending on the concentration of the inhibitor, its specificity and its site of action in the pancreatic acinar cell. These observations elucidate some of the complex relations between cysteine and serine proteases in the pancreas with respect to their mechanisms of activation, their subcellular sites of action, and their possible role in the onset of pancreatitis.
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PMID:The role of cysteine proteases in intracellular pancreatic serine protease activation. 1084 66

Hereditary pancreatitis has been found to be associated with germline mutations in the cationic trypsinogen (PRSS1) gene. Here we report a family with hereditary pancreatitis that carries a novel PRSS1 mutation (R122C). This mutation cannot be diagnosed with the conventional screening method using AflIII restriction enzyme digest. We therefore propose a new assay based on restriction enzyme digest with BstUI, a technique that permits detection of the novel R122C mutation in addition to the most common R122H mutation, and even in the presence of a recently reported neutral polymorphism that prevents its detection by the AflIII method. Recombinantly expressed R122C mutant human trypsinogen was found to undergo greatly reduced autoactivation and cathepsin B-induced activation, which is most likely caused by misfolding or disulfide mismatches of the mutant zymogen. The K(m) of R122C trypsin was found to be unchanged, but its k(cat) was reduced to 37% of the wild type. After correction for enterokinase activatable activity, and specifically in the absence of calcium, the R122C mutant was more resistant to autolysis than the wild type and autoactivated more rapidly at pH 8. Molecular modeling of the R122C mutant trypsin predicted an unimpaired active site but an altered stability of the calcium binding loop. This previously unknown trypsinogen mutation is associated with hereditary pancreatitis, requires a novel diagnostic screening method, and, for the first time, raises the question whether a gain or a loss of trypsin function participates in the onset of pancreatitis.
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PMID:Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 --> Cys) that alters autoactivation and autodegradation of cationic trypsinogen. 1171 9

This review provides some aspects on the physiology of stimulation and inhibition of pancreatic digestive enzyme secretion and the pathophysiology of pancreatic acinar cell function leading to pancreatitis. Cholecystokinin (CCK) stimulates both directly via CCK-A receptors on acinar cells and indirectly via CCK-B receptors on nerves, followed by acetylcholine release, pancreatic enzyme secretion. It is still not known whether CCK-A receptors exist in human acinar cells, in contrast to acinar cells of rodents where CCK-A receptors have been well described. CCK has numerous actions both in the periphery and in the central nervous systems. CCK inhibits gastric motility and regulates satiety. Another major function of CCK is stimulation of gallbladder contraction. This function enables that bile acids act simultaneously with pancreatic lipolytic enzymes. Secretin is a major stimulator of bicarbonate secretion. Trypsinogen is activated by the gut mucosal enzyme enterokinase. The other pancreatic proenzymes are activated by trypsin. Termination of enzyme secretion may be regulated by negative feedback mechanisms via destruction of CCK-releasing peptides by trypsin. Furthermore, the ileum may act as a brake by release of inhibitory hormones such as PYY and somatostatin. In the pathophysiology of acute pancreatitis, fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen is regarded as an initiation step. This activation of trypsinogen may be caused by the lysosomal enzyme cathepsin B. However, autoactivation of trypsinogen itself may be a possibility in pathogenesis. Autoactivation is enhanced in certain mutations of trypsinogen. Furthermore, an imbalance of protease inhibitors and active proteases may be involved. The role of pancreatic lipolytic enzymes, the role of bicarbonate secretion, and toxic Ca(2+) signals by excessive liberation from the endoplasmic reticulum have to be discussed in the pathogenesis of acute pancreatitis.
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PMID:New advances in cell physiology and pathophysiology of the exocrine pancreas. 2152 56

The domestic ferret (Mustela putorius furo) recently emerged as a novel model for human pancreatic diseases. To investigate whether the ferret would be appropriate to study hereditary pancreatitis associated with increased trypsinogen autoactivation, we purified and cloned the trypsinogen isoforms from the ferret pancreas and studied their functional properties. We found two highly expressed isoforms, anionic and cationic trypsinogen. When compared to human cationic trypsinogen (PRSS1), ferret anionic trypsinogen autoactivated only in the presence of high calcium concentrations but not in millimolar calcium, which prevails in the secretory pathway. Ferret cationic trypsinogen was completely defective in autoactivation under all conditions tested. However, both isoforms were readily activated by enteropeptidase and cathepsin B. We conclude that ferret trypsinogens do not autoactivate as their human paralogs and cannot be used to model the effects of trypsinogen mutations associated with human hereditary pancreatitis. Intra-pancreatic trypsinogen activation by cathepsin B can occur in ferrets, which might trigger pancreatitis even in the absence of trypsinogen autoactivation.
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PMID:Trypsinogen isoforms in the ferret pancreas. 3030 76

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