Regulation and Physiological Roles of Human Tryptase in the Secretary Granules of Mast Cells

人类胰蛋白酶家族在肥大细胞中选择性表达。β-类胰蛋白酶基因的产物在肝素蛋白聚糖存在下在酸性pH下从原酶自动催化加工成原酶，在二肽基肽酶I存在下在酸性pH下从原酶自动催化加工成成熟肽，并且在肝素存在下在酸性pH下通过自发构象改变自动催化加工成具有酶活性的四聚体。Β-类胰蛋白酶在酸性pH下通过肝素稳定，并且对丝氨酸蛋白酶的生物抑制剂具有抗性。在不存在肝素的情况下，β-类胰蛋白酶在中性pH下自发失活，因为它形成单体，而在酸性pH下，在存在和不存在肝素的情况下，无活性单体自发重新形成活性四聚体。四聚体形成和再活化的最适pH为6左右，表明His残基起关键作用。酶的这些物理化学性质是否与其在体内的调节方式有关尚不确定。在这方面，发现人β-类胰蛋白酶具有最适合于肝素蛋白聚糖和C3裂解以及自动加工的酸性pH。这种性质可能将体内最佳活性限制在具有酸性pH的组织或粘膜部位，如炎症和伤口愈合部位，或如气道。应考虑人β-类胰蛋白酶的再活化是否发生在细胞外或细胞内位点（体内pH为酸性）。

The human tryptase family is selectively expressed in mast cells. Products of β-tryptase gene (s) are autocatalytically processed from the pro- to the pro' enzyme at acidic pH in the presence of heparin proteoglycan, from the pro' to the mature peptide at acidic pH by dipeptidyl peptidase I, and to the enzymatically active tetramer by spontaneous conformational alterations at acidic pH in the presence of heparin. Β-Tryptase is stabilized at acidic pH by heparin, and is resistant to biologic inhibitors of serine proteases. In the absence heparin, β-tryptase spontaneously inactivates at neutral pH as it forms monomers, while at acidic pH the inactive monomers spontaneously re-form the active tetramer both in the presence and in the absence of heparin. The optimal pH for tetramer formation and reactivation is about 6, sugessting His residues play a critical role. Whether these physicochemical properties of the enzyme relate to how it is regulated in vivo is uncertain. In this regard, human β-tryptase was found to have an acidic pH optimum for cleavage of heparin proteoglycan and C3, as well as for autoprocessing. This property might restrict optimal activity in vivo to tisse or mucosal sites with an acidic pH, such as sites of inflammation and wound healing, or such as the airway. Whether reactivation of human β-tryptase occurs at extracellular or intracellular sites, where the pH is acidic in vivo, should be considered.