The pathobiochemistry of hereditary pancreatitis: studies on recombinant human cationic trypsinogen.
OBJECTIVE
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.
Sahin-Tóth
M
M
Department of Physiology, University of California Los Angeles, Calif., USA. miklos@hhmi.ucla.edu
D001329:Autolysis; D002384:Catalysis; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007700:Kinetics; D010195:Pancreatitis / Q000235:genetics* / Q000473:pathology*; D011994:Recombinant Proteins / Q000235:genetics; D014357:Trypsin / Q000378:metabolism; D014362:Trypsinogen / Q000235:genetics*
D011994:Recombinant Proteins; C064831:PRSS2 protein, human; D014362:Trypsinogen; D014357:Trypsin