Human Cationic Trypsinogen ROLE OF Asn-21 IN ZYMOGEN ACTIVATION AND IMPLICATIONS IN HEREDITARY PANCREATITIS
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摘要: Mutation Asn-21 --> Ile in human cationic trypsinogen (Tg-1) has been associated with hereditary pancreatitis. Recent studies rat anionic Tg (Tg-2) indicated that the analogous Thr-21 mutation stabilizes zymogen against autoactivation, whereas it no effect on catalytic properties or autolytic stability of trypsin (Sahin-Toth, M. (1999) J. Biol. Chem. 274, 29699-29704). In present paper, (Asn-21-Tg) and mutants (Ile-21-Tg) Thr (Thr-21-Tg) were expressed Escherichia coli, activation, degradation, autolysis studied. Enterokinase activated Asn-21-Tg approximately 2-fold better than Ile-21-Tg Thr-21-Tg, parameters trypsins comparable. At 37 degrees C, 5 mm Ca(2+), all three highly stable. absence Asn-21- Ile-21-trypsins suffered an indistinguishable manner, Thr-21-trypsin exhibited significantly increased stability. sharp contrast to observations proenzyme, at pH 8.0, autoactivation kinetics identical; however, 5. 0, autoactivated enhanced rate relative Asn-21-Tg. Remarkably, both values, Thr-21-Tg showed markedly higher rates two other zymogens. Finally, autocatalytic proteolysis zymogens was limited cleavage Arg-117, digestion Lys-188 detected. The indicate stabilization by Ile-21 as observed Tg-2 is not characteristic Tg-1. Instead, propensity under acidic conditions might be relevant pathomechanism same context, faster caused Tg-1 provide a rationale for evolutionary divergence from found mammalian trypsinogens.
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