Carrell R W, Whisstock J, Lomas D A
Department of Haematology, University of Cambridge, United Kingdom.
Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 2):S171-5. doi: 10.1164/ajrccm/150.6_Pt_2.S171.
alpha 1-Antitrypsin is a member of the serine proteinase inhibitor, serpin, family of protease inhibitors, which have their reactive centers situated on a mobile peptide loop. This reactive loop can adopt varied conformations and perturbations of molecular structure to allow the pathological linking of the loop of one molecule to a beta-pleated sheet of another. This linkage has been shown to be the cause of the polymerization and aggregation within the hepatocyte of the common Z mutant of antitrypsin. The occurrence of loop-sheet polymerization has been confirmed with other deficiency variants of antitrypsin that accumulate in the liver (Mmalton, Siiyama) and also shown to occur in pathological mutants of C1-inhibitor and antithrombin. Deductive evidence indicates that the loop is inserted into the A-sheet of the next molecule, but recent structural findings raise the possibility of insertion into the C-sheet. This detail of loop-sheet polymerization is important for the design of strategies to interfere with insertion and hence lesson the accumulation of Z antitrypsin that is responsible for associated liver damage.
α1-抗胰蛋白酶是丝氨酸蛋白酶抑制剂家族（serpin）的成员，该家族的蛋白酶抑制剂的反应中心位于一个可移动的肽环上。这个反应环可以呈现不同的构象并发生分子结构的扰动，从而使一个分子的环与另一个分子的β折叠片发生病理性连接。这种连接已被证明是抗胰蛋白酶常见Z突变体在肝细胞内发生聚合和聚集的原因。抗胰蛋白酶其他在肝脏中积累的缺陷变体（Mmalton、Siiyama）也证实了环-片层聚合的发生，并且在C1抑制剂和抗凝血酶的病理性突变体中也有发生。推断证据表明该环插入到下一个分子的A片层中，但最近的结构研究结果提出了插入到C片层的可能性。环-片层聚合的这一细节对于设计干扰插入的策略很重要，从而减少导致相关肝损伤的Z抗胰蛋白酶的积累。
