Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyacrylamide gel electrophoresis of pure pancreatic juice from 14 healthy normal subjects, 11 chronic alcoholics without detectable pancreatic disease, 15 patients with pancreatitis, and two with cancer of the pancreas consistently demonstrated the presence of two variants of trypsinogen with different electrophoretic mobilities. In healthy normal subjects the proportion of cationic to anionic trypsinogen was invariably greater than 1 and averaged about 2. In chronic alcoholics, patients with pancreatitis or cancer of the pancreas, this ratio, with a single exception, was below one and averaged about 0.45. The extraordinary consistency of these findings suggests that the quantitative relationship between cationic and anionic trypsinogen in human pancreatic juice may be a very sensitive indicator of incipient or existing pancreatic pathology. The most acceptable explanation for the reversal of the normal zymogen ratio in pancreatic disease is a selective increase in the synthesis of the anionic variant relative to that of the cationic species. Total trypsinogen concentrations differed widely from one another in the three patient groups, but the ratio of cationic to anionic trypsinogen exhibited little change and remained below 1. Our results also demonstrate for the first time a specific effect of chronic alcohol abuse on the secretory profile of a pancreatic enzyme in human subjects. A newly discovered minor, trypsinogen-like component of human pancreatic juice was found to be significantly increased in pancreatic juice of chronic alcoholics, decreased in pancreatic secretions of patients with pancreatitis, and barely detectable in those of two patients with cancer of the pancreas.
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PMID:Trypsinogen variants in pancreatic juice of healthy volunteers, chronic alcoholics, and patients with pancreatitis and cancer of the pancreas. 53

Graft pancreatitis and allograft rejection were both accompanied by increased serum levels of immunoreactive anionic trypsin (irAT) in a porcine pancreatic allograft transplantation model. Characterization of this immunoreactivity by gel filtration revealed different elution profiles in these conditions that can be helpful in the differentiation between them. During graft pancreatitis, a major part of the immunoreactivity was found within the high-molecular-weight fraction corresponding to the formation of complexes between trypsin and protease inhibitors. During allograft rejection, virtually all serum irAT increase could be attributed to the release of anionic trypsinogen without any evidence of activation. Since this transplantation model includes urinary diversion of the exocrine secretions, irAT and immunoreactive cationic trypsin (irCT) can also be measured in the urine. Characterization of this immunoreactivity showed that most of both irAT and irCT was found as active trypsin but a minor part was probably complexed with some protease inhibitor (possibly pancreatic secretory trypsin inhibitor [PSTI]).
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PMID:Characterization of immunoreactive trypsin as a means of differentiating graft pancreatitis and allograft rejection after porcine pancreatic transplantation. 173 80

Human trypsinogens 1 and 2 were activated at the same rate by pure human cathepsin B at pH 3.8. Human trypsinogen 1 was also spontaneously activated during incubation at acidic pH, activation being most rapid at pH 5.0. In contrast, trypsinogen 2 showed little or no activation under these conditions. The presence of calcium salts (20mM) delayed the onset of activation under all conditions tested. These findings support the proposal that premature activation of the pancreatic zymogens may result from their entry into the lysosomal system in pancreatitis.
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PMID:Possible lysosomal activation of pancreatic zymogens. Activation of both human trypsinogens by cathepsin B and spontaneous acid. Activation of human trypsinogen 1. 320 69

The N21I missense mutation in the cationic trypsinogen gene is the second most frequent mutation in hereditary pancreatitis (HP). In this article, we suggest that the N21I mutation most likely arose as a gene conversion event in which the functional anionic trypsinogen gene acted as the donor sequence. This hypothesis is supported by the unique presence of Ile at residue 21 of the anionic gene amongst the several highly homologous trypsinogen genes; a single unbroken tract of nucleotides of up to 113 bp flanking the I21 residue in the anionic trypsinogen gene; and the presence of a chi-like sequence in the 5' proximity and a palindromic sequence in the 3' vicinity of the N21I mutation. Furthermore, a multiple alignment of the partial amino acid sequence of vertebrate trypsins around residue 21 indicated that N21 and I21 may represent advantageously selected mutations of the two functional human trypsinogen genes in evolutionary history. These observations, which are complementary to the previous findings, provide further insights into the genetic mechanism and pathogenic role of the N21I mutation in HP.
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PMID:Origin and implication of the hereditary pancreatitis-associated N21I mutation in the cationic trypsinogen gene. 1098 92

We recently experienced a rare case of chronic pancreatitis in a 13-year-old Japanese boy. Recently, in hereditary pancreatitis patients, some mutations have been identified in the trypsinogen gene. The purpose of this study was to investigate whether the same mutations could also be found in this patient. Polymerase chain reaction (PCR)-amplified products of his cationic and anionic trypsinogen genes were examined by direct sequence analysis. The gene analysis failed to show any mutation in any exons and their flanking intronic sequences of his trypsinogen genes. These findings indicate that the chronic calcifying pancreatitis in the present patient is "idiopathic", and thus a rare case of juvenile pancreatitis.
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PMID:Idiopathic calcifying pancreatitis in a Japanese pediatric patient. 1157 32

Rat P23 is an isoform of trypsin (ogens) synthesized by rat acinar cells. Expression of P23 is stimulated strongly by caerulein, an analogue of cholecystokinin (CCK). However, the physiological relevance of rat P23 in healthy and pathological conditions such as caerulein-induced pancreatitis is largely unknown. Using recombinant P23 trypsinogen and reconstitution analysis of zymogen autoactivation, unique inhibitor-resistance characteristics of P23 were elucidated. P23 cDNA was expressed in Escherichia coli periplasm, yielding recombinant P23 trypsinogen. Autoactivation of zymogen granule contents from caerulein-induced rat pancreas was also studied. Activation kinetics of P23 by enterokinase was similar to those of rat anionic trypsinogen, which is a major isoform of trypsinogen. Interestingly, rat pancreatic secretory trypsin inhibitor (PSTI), which protects against deleterious activation of trypsinogens in zymogen granules, failed to inhibit P23 trypsin even with four-fold molar excess, at which concentration it effectively inhibited rat anionic trypsin to almost 100%. P23 trypsin also showed marked resistance to proteinaceous trypsin inhibitors such as soybean trypsin inhibitor and aprotinin. P23 trypsin activated by enterokinase dramatically accelerated the cascade of autoactivation of anionic trypsinogen even in the presence of PSTI. Taken together with a previous observation that P23 is specifically upregulated 14-fold by 24-h caerulein infusion, these results suggest that elevated levels of P23 should be taken into consideration in the mechanism of trypsinogens within the pancreas in pathological conditions.
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PMID:Expression and functional analysis of rat P23, a gut hormone-inducible isoform of trypsin, reveals its resistance to proteinaceous trypsin inhibitors. 1238 73

Human pancreatic secretions contain two major trypsinogen isoforms, cationic and anionic trypsinogen, normally at a ratio of 2 : 1. Pancreatitis, pancreatic cancer and chronic alcoholism lead to a characteristic reversal of the isoform ratio, and anionic trypsinogen becomes the predominant zymogen secreted. To understand the biochemical consequences of these alterations, we recombinantly expressed and purified both human trypsinogens and documented characteristics of autoactivation, autocatalytic degradation and Ca2+-dependence. Even though the two trypsinogens are approximately 90% identical in their primary structure, we found that human anionic trypsinogen and trypsin exhibited a significantly increased (10-20-fold) propensity for autocatalytic degradation, relative to cationic trypsinogen and trypsin. Furthermore, in contrast to the characteristic stimulation of the cationic proenzyme, acidic pH inhibited autoactivation of anionic trypsinogen. In mixtures of cationic and anionic trypsinogen, an increase in the proportion of the anionic proenzyme had no significant effect on the levels of trypsin generated by autoactivation or by enterokinase at pH 8.0 in 1 mm Ca2+- conditions that were characteristic of the pancreatic juice. In contrast, rates of trypsinogen activation were markedly reduced with increasing ratios of anionic trypsinogen under conditions that were typical of potential sites of pathological intra-acinar trypsinogen activation. Thus, at low Ca2+ concentrations at pH 8.0, selective degradation of anionic trypsinogen and trypsin caused diminished trypsin production; while at pH 5.0, inhibition of anionic trypsinogen activation resulted in lower trypsin yields. Taken together, the observations indicate that up-regulation of anionic trypsinogen in pancreatic diseases does not affect physiological trypsinogen activation, but significantly limits trypsin generation under potential pathological conditions.
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PMID:Human anionic trypsinogen: properties of autocatalytic activation and degradation and implications in pancreatic diseases. 1270 65

The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen. To date, 19 genetic variants have been identified in the cationic trypsinogen gene (PRSS1) of patients with hereditary, familial, or sporadic chronic pancreatitis. A common feature of cationic trypsinogen mutants studied so far is an increased propensity for autocatalytic activation (autoactivation). This is thought to lead to premature intrapancreatic digestive protease activation. In contrast, no pancreatitis-associated mutations have been found in the anionic trypsinogen gene (PRSS2), suggesting that this isoform might play a relatively unimportant role in pancreatitis. To challenge this notion, here we describe the unique properties of the E79K cationic trypsinogen mutation (c.235G>A), which was identified in three European families affected by sporadic or familial pancreatitis cases. In vitro analysis of recombinant wild-type and mutant enzymes revealed that catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor was unaffected. Although the E79K mutation introduces a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. Furthermore, in contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen two-fold better than wild-type cationic trypsin did, while the common pancreatitis-associated mutants R122H or N29I had no such effect. The observations not only suggest a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlight the importance of interactions between the two major trypsinogen isoforms in the development of genetically determined chronic pancreatitis.
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PMID:Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2). 1469 29

One of ostrich (Struthio camelus) trypsinogen genes was cloned from pancreatic cDNA. Its amino acid sequence compared to known trypsin sequences from other species shows high identity and suggests that it is a member of the phylogenetically anionic trypsinogen I subfamily. After cytoplasmic over expression in Escherichia coli and renaturation, the activation properties of ostrich trypsinogen were studied and compared to those of human trypsinogen 1 (also called as human cationic trypsinogen). Ostrich trypsinogen undergoes bovine enterokinase activation and autoactivation much faster than human trypsinogen 1 and exhibits on a synthetic substrate a somewhat higher enzymatic activity than the latter one. The most interesting property of ostrich trypsin is its relatively fast autolysis that can be explained via a mechanism different from the common mechanism for rat and human 1 trypsins. The latter proteases have a site, Arg117-Val118, where the autolysis starts and then goes on in a zipper-like fashion. This is absent from ostrich trypsin. Instead it has a couple of cleavage sites within regions 67-98, including two unusual ones, Arg76-Glu77 and Arg83-Ser84. These appear to be hydrolysed fast in a non-consecutive manner. Such an autolysis mechanism could not be inhibited by a single-site mutation which in humans is proposed to lead to pancreatitis.
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PMID:Cloning and expression of ostrich trypsinogen: an avian trypsin with a highly sensitive autolysis site. 1575 90

Hereditary pancreatitis, an autosomal dominant disease with approximately 80% penetrance, can be caused by both 'gain-of-function' missense and copy number mutations in the cationic trypsinogen gene (PRSS1). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/PRSS1 gene in a French white family with hereditary pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3-5 from PRSS1, apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent 'double gain-of-function' effect, acting simultaneously as a 'quantitative' copy number mutation and a 'qualitative' missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.
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PMID:Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. 1846 67


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