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The pathobiochemistry of hereditary pancreatitis: studies on recombinant human cationic trypsinogen
1Department of Physiology, University of California Los Angeles, Calif., USA. miklos@hhmi.ucla.edu
Background/Aims:
This study attempts to identify the biochemical alterations in human cationic trypsinogen and trypsin caused by the hereditary pancreatitis-associated mutations Arg117-->His and Asn21-->Ile.
Methods:
Recombinant wild-type and mutant human cationic trypsinogens were expressed in Escherichia coli and purified to homogeneity, and trypsin autolysis and trypsinogen autoactivation were characterized.
Results:
Both mutations significantly enhanced the autoactivation of human cationic trypsinogen. In addition, the Arg117-->His mutation inhibited autocatalytic inactivation of trypsin, while the Asn21-->Ile mutation had no such effect.
Conclusions:
The findings support the notion that enhanced trypsinogen activation in the pancreas is the common initiating step in hereditary pancreatitis, whereas trypsin stabilization plays a role in cases associated with the Arg117-->His mutation.
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