CHYMOTRYPSIN C CO-ACTIVATION OF HUMAN PANCREATIC PROCARBOXYPEPTIDASES A1 AND A2

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 人消化羧肽酶CPA1、CPA2和CPB1是由胰腺分泌的一种含有94-96个氨基酸的长前肽的非活性前体酶。原羧基肽酶的激活是通过胰酶对前肽C末端的蛋白水解性裂解来启动的。在这项研究中，我们证明了胰凝乳酶C(CTRC)随后切割前肽可以诱导胰酶激活的CPA1和CPA2活性增加近10倍，而CPB1活性不受影响。其他人胰腺蛋白如糜蛋白酶B1、糜蛋白酶B2、类糜蛋白酶-1、弹力酶2A、弹力酶3A或弹力酶3B在促进原羧基肽酶激活方面没有活性或明显效果较差。在这些观察的基础上，我们认为CTRC是proCPA1和proCPA2的生理共激活剂。此外，这些结果证实并扩展了CTRC是消化酶原激活的关键调节因子的概念。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Human digestive carboxypeptidases CPA1, CPA2 and CPB1 are secreted by the pancreas as inactive proenzymes containing a 94-96 amino-acid long propeptide. Activation of procarboxypeptidases is initiated by proteolytic cleavage at the C-terminal end of the propeptide by trypsin. In this study, we have demonstrated that subsequent cleavage of the propeptide by chymotrypsin C (CTRC) induces a nearly 10-fold increase in the activity of trypsin-activated CPA1 and CPA2, whereas CPB1 activity is unaffected. Other human pancreatic proteases such as chymotrypsin B1, chymotrypsin B2, chymotrypsin-like enzyme-1, elastase 2A, elastase 3A or elastase 3B were found to be inactive or markedly less effective at promoting procarboxypeptidase activation. On the basis of these observations we propose that CTRC is a physiological co-activator of proCPA1 and proCPA2. Furthermore, the results confirm and extend the notion that CTRC is a key regulator of digestive zymogen activation.