Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.
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PMID:A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. 1669 18

Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
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PMID:Hereditary chronic pancreatitis. 1720 47

Hereditary chronic pancreatitis (HCP) is a very rare form of early-onset chronic pancreatitis. Apart from young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. Diagnostic criteria and treatment of HCP also resemble those of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile-duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, the disease is mild in most patients. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation, disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes--such as the anionic trypsinogen (PRSS2), the serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR)--have also been found to be associated with chronic pancreatitis (idiopathic and hereditary). Genetic testing should only be performed in carefully selected patients by direct DNA sequencing, and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications such as pseudocysts and bile-duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. The risk of pancreatic cancer is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
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PMID:Hereditary chronic pancreatitis. 1820 17

Tropical calcific pancreatitis (TCP) is a subtype of chronic pancreatitis which is unique to tropical regions. Patients present at young age with recurrent abdominal pain, nutritional deficiencies, and insulin-requiring diabetes. For a long time, the aetiology of this disorder was poorly understood. Several environmental factors, such as malnutrition or the consumption of toxic food components such as cyanogenic glycosides, were proposed as pathogenic factors. In the last decade, a major impact on the understanding of the aetiology of TCP has come from genetic studies on hereditary and idiopathic chronic pancreatitis. Genetic alterations in at least five genetic loci are clearly associated with chronic pancreatitis in the Western world. These include alterations in genes coding for trypsinogens, the most abundant digestive enzymes (PRSS1 and PRSS2), the trypsin inhibitor (SPINK1) and the trypsin-degrading enzyme, chymotrypsinogen C (CTRC). In addition, alterations in the cystic fibrosis (CFTR) gene are associated with idiopathic pancreatitis. TCP clinically resembles non-alcoholic chronic pancreatitis of Western countries, suggesting that similar genetic defects might also be of importance in this disease entity. Indeed, alterations in at least two genes, SPINK1 and CTRC, are strongly associated with TCP. The current review focuses on the recent developments in the understanding of the genetic basis of inherited pancreatitis, with special emphasis on TCP.
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PMID:Genetic aspects of tropical calcific pancreatitis. 1860 51

Human pancreatic trypsinogens undergo post-translational sulfation on Tyr(154), catalysed by the Golgi-resident enzyme tyrosylprotein sulfotransferase 2. Sequence alignments suggest that the sulfation of Tyr(154) is facilitated by a unique sequence context which is characteristically found in primate trypsinogens. In the search for genetic variants that might alter this sulfation motif, we identified a single nucleotide polymorphism (c.457G>C) in the PRSS2 (serine protease 2, human anionic trypsinogen) gene, which changed Asp(153) to a histidine residue (p.D153H). The p.D153H variant is common in subjects of African origin, with a minor allele frequency of 9.2%, whereas it is absent in subjects of European descent. We demonstrate that Asp(153) is the main determinant of tyrosine sulfation in anionic trypsinogen, as both the natural p.D153H variation and the p.D153N mutation result in a complete loss of trypsinogen sulfation. In contrast, mutation of Asp(156) and Glu(157) only slightly decrease tyrosine sulfation, whereas mutation of Gly(151) and Pro(155) has no effect. With respect to the biological relevance of the p.D153H variant, we found that tyrosine sulfation had no significant effect on the activation of anionic trypsinogen or the catalytic activity and inhibitor sensitivity of anionic trypsin. Taken together with previous studies, the observations of the present study suggest that the primary role of trypsinogen sulfation in humans is to stimulate autoactivation of PRSS1 (serine protease 1, human cationic trypsinogen), whereas the sulfation of anionic trypsinogen is unimportant for normal digestive physiology. As a result, the p.D153H polymorphism which eliminates this modification could become widespread in a healthy population.
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PMID:A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2). 1898 5

In the past, chronic pancreatitis has been regarded as a fairly uniform and largely untreatable disorder that most commonly affects patients who both lack gainful employment or adequate insurance coverage and have a tendency to smoke and drink. Large clinical trials suggest that this perception is not only misguided and discriminatory but also not based on facts. We forgot that the perception of chronic liver disease was similar before World War II, and just like liver cirrhosis the fibrosis and cirrhosis of the pancreas--i.e. chronic pancreatitis--is the end result of a range of environmental, inflammatory, infectious and genetic disorders. A growing number of these have only recently been recognized as a distinct entity and several of which are becoming truly treatable. A large proportion of the risk for developing pancreatitis is conveyed by genetic risk factors, and we estimate that less than half of those have been identified so far. The same holds true for protective factors that can prevent pancreatitis, even in the face of excessive alcohol abuse. Various gene mutations and polymorphisms appear to determine an individual's susceptibility for developing pancreatic disease, for the severity of the disease, and for the disease progression. The spectrum of genotype/phenotype associations ranges from straightforward autosomal dominant traits with near-complete penetrance, as for the most common mutations in the cationic trypsinogen gene (PRSS1), to moderate risks factors without mendelian inheritance patterns, as for SPINK1 and CFTR mutations, to very subtle risk associations and disease modifiers that can only be identified in large cohort studies, as for the chymotrypsin C, calcium-sensing receptor and the anionic trypsin (PRSS2) mutations. Only a better understanding of the disease mechanisms that underlie these changes will make an individualized therapy of pancreatic disorders a realistic option.
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PMID:Advances in the etiology of chronic pancreatitis. 2081 6

It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain-of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15-40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of-function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25-30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively.
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PMID:Genetics of pancreatitis: a guide for clinicians. 2152 53