title: Trypsinogen stabilization by mutation Arg117-->His: a unifying pathomechanism for hereditary pancreatitis?
abstract: Mutations Arg117-->His and Asn21-->Ile of the human cationic trypsinogen have been recently identified in patients affected by hereditary pancreatitis (HP). The Arg117-->His substitution is believed to cause pancreatitis by eliminating an essential autolytic cleavage site in trypsin, thereby rendering the protease resistant to inactivation through autolysis. Here we demonstrate that the Arg117-->His mutation also significantly inhibits autocatalytic trypsinogen breakdown under Ca(2+)-free conditions and stabilizes the zymogen form of rat trypsin. Taken together with recent findings demonstrating that the Asn21-->Ile mutation stabilizes rat trypsinogen against autoactivation and consequent autocatalytic degradation, the observations suggest a unifying molecular pathomechanism for HP in which zymogen stabilization plays a central role.
authors.affiliation: Department of Physiology, University of California Los Angeles, Los Angeles, California, 90095-1662, USA. miklos@hhmi.ucla.edu
authors.forename: M
authors.initials: M
authors.lastname: Sahin-Tóth
authors.forename: L
authors.initials: L
authors.lastname: Gráf
authors.forename: M
authors.initials: M
authors.lastname: Tóth
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D004591:Electrophoresis, Polyacrylamide Gel; D004765:Enteropeptidase; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010195:Pancreatitis / Q000201:enzymology / Q000235:genetics*; D051381:Rats; D014357:Trypsin / Q000235:genetics; D014362:Trypsinogen / Q000737:chemistry / Q000235:genetics*
chemical_list: D014362:Trypsinogen; D001120:Arginine; D014357:Trypsin; D004765:Enteropeptidase