Linked Life Data

14695529

Source:http://linkedlifedata.com/resource/pubmed/id/14695529

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2003-12-25
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1098-1004
pubmed:author
pubmed:copyrightInfo
Copyright 2003 Wiley-Liss, Inc.
pubmed:issnType
Electronic
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
22-31
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:14695529-Adult, pubmed-meshheading:14695529-Aged, pubmed-meshheading:14695529-Carrier Proteins, pubmed-meshheading:14695529-Catalysis, pubmed-meshheading:14695529-Cathepsins, pubmed-meshheading:14695529-Chronic Disease, pubmed-meshheading:14695529-DNA Mutational Analysis, pubmed-meshheading:14695529-Enzyme Activation, pubmed-meshheading:14695529-Female, pubmed-meshheading:14695529-Humans, pubmed-meshheading:14695529-Intercellular Signaling Peptides and Proteins, pubmed-meshheading:14695529-Isoenzymes, pubmed-meshheading:14695529-Kinetics, pubmed-meshheading:14695529-Male, pubmed-meshheading:14695529-Middle Aged, pubmed-meshheading:14695529-Mutation, pubmed-meshheading:14695529-Pancreatitis, pubmed-meshheading:14695529-Pedigree, pubmed-meshheading:14695529-RNA, Messenger, pubmed-meshheading:14695529-Trypsin, pubmed-meshheading:14695529-Trypsinogen
pubmed:year
2004
pubmed:articleTitle
Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2).
pubmed:affiliation
Medizinische Klinik und Poliklinik II, Universität Leipzig, Leipzig, Germany.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't