The main objective of this exploratory grant is to investigate the hypothesis that alcoholic pancreatitis is caused by premature intrapancreatic trypsinogen activation, as a result of altered post-translational modification of trypsinogen. We propose that alcohol might alter the functional properties of trypsin(ogen) by affecting the extent of post-translational sulfation of a tyrosyl sidechain on the surface of the trypsinogen molecule. This aberrant trypsinogen would result in ? enhanced trypsinogen activation or increased trypsin stability in the pancreas. This hypothesis draws support from our recent knowledge that hereditary pancreatitis-associated mutations in the cationic trypsinogen result in atypical trypsinogen molecules, which exhibit faster activation or higher stability. We propose that ethanol-induced changes in the post-translational sulfation of human trypsinogens might mimic the effects of certain hereditary pancreatitis-associated mutations, and cause alcoholic pancreatitis. Our major specific aims are to (1) characterize the posttranslational modifying group on human trypsinogens; (2) examine the functional consequences of post-translational sulfation of human trypsinogens; (3) develop a facile method to monitor the extent of post-translational sulfation of trypsinogens, and (4) investigate how trypsinogen sulfation is altered in alcoholic and idiopathic chronic pancreatitis. ? ? ?
| Rosendahl, Jonas; Ronai, Zsolt; Kovacs, Peter et al. (2010) Sequence analysis of the human tyrosylprotein sulfotransferase-2 gene in subjects with chronic pancreatitis. Pancreatology 10:165-72 |
| Rónai, Zsolt; Witt, Heiko; Rickards, Olga et al. (2009) A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2). Biochem J 418:155-61 |
| Sahin-Toth, Miklos; Kukor, Zoltan; Nemoda, Zsofia (2006) Human cationic trypsinogen is sulfated on Tyr154. FEBS J 273:5044-50 |
