title: Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2).
abstract: 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.
authors.affiliation: Medizinische Klinik und Poliklinik II, Universität Leipzig, Leipzig, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Teich
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Maréchal
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kukor
authors.forename: Karel
authors.initials: K
authors.lastname: Caca
authors.forename: Helmut
authors.initials: H
authors.lastname: Witzigmann
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Joachim
authors.initials: J
authors.lastname: Mössner
authors.forename: Volker
authors.initials: V
authors.lastname: Keim
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
mesh_terms: D000328:Adult; D000368:Aged; D002352:Carrier Proteins; D002384:Catalysis; D002403:Cathepsins / Q000378:metabolism; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010195:Pancreatitis / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000096:biosynthesis; D014357:Trypsin / Q000378:metabolism; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; C486642:SPINK1 protein, human; C064831:PRSS2 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen; D002403:Cathepsins; C489303:PRSS1 protein, human; D014357:Trypsin