Molecular evolution of serpins: homologous structure of the human alpha 1-antichymotrypsin and alpha 1-antitrypsin genes.
Molecular evolution of serpins: homologous structure of the human alpha 1-antichymotrypsin and alpha 1-antitrypsin genes.
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丝氨酸蛋白酶抑制剂的分子进化：人类α1-抗胰蛋白酶和α1-抗胰蛋白酶基因的同源结构。
DOI：
10.1021/bi00398a033
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发表时间：
1987
期刊：
影响因子：
2.9
通讯作者：
Woo,SL
中科院分区：
文献类型：
--
作者：
Bao,JJ;Sifers,RN;Kidd,VJ;Ledley,FD;Woo,SL
摘要：抗胰凝乳蛋白酶属于超基因家族，包括抗胰蛋白酶、抗凝血酶III、卵清蛋白和血管紧张素原。已克隆了人染色体arantichymotrypsin基因，并建立了其分子结构。该基因长约12 kb，包含5个外显子和4个内含子。arantichymotrypsin基因内内含子的位置与人arantitrypsin和angiotensinogen基因的位置相同。这个超基因家族的其他成员含有位于基因非同源位置的内含子。aranti-chymotrypsin和arantitrypsin基因的同源组织对应于它们的蛋白质序列之间的高度同源性，并表明这些位点是由最近的基因重复引起的。一个模型的基因组结构和蛋白质序列的丝氨酸蛋白酶抑制剂超家族的进化。抗胰凝乳蛋白酶（ACT）是对胰凝乳蛋白酶样酶具有亲和力的血浆丝氨酸蛋白酶抑制剂（Travis等人，1978 a，B）。其靶底物包括嗜中性组织蛋白酶G、肥大细胞糜酶和在体外将血管紧张素I转化为生物活性血管收缩剂血管紧张素II的蛋白酶（Reilly et al.，1982; Wintroub等人，1981; Tonnensen等人，1982年）。它是一种68000道尔顿的糖蛋白，并且在结构上与阿抗胰蛋白酶（AAT）相关（Morii & Travis，1983 a，B），阿抗胰蛋白酶是嗜中性粒细胞弹性蛋白酶的特异性抑制剂，并且保护肺弹性蛋白纤维免受该蛋白酶的降解（Olsen等人，1975; Tuttle & Jones，1975）。ACT的生理功能尚未明确定义。然而，已经表明嗜中性组织蛋白酶G增强了嗜中性弹性蛋白酶消化弹性蛋白的速率（Reilly & Travis，1978），并且ACT选择性地集中在慢性感染患者的支气管腔中（赖利& Brogan，1972）。因此，ACT可能参与维持肺中的整体蛋白酶-抗蛋白酶平衡。ACT还显示可显著降低T细胞杀伤淋巴细胞的天然细胞毒性活性（Graragha et al，1982），推测是通过与这些细胞表面的胰凝乳蛋白酶样酶结合。此外，它是肝细胞癌的敏感标志物（Orodonez & Manning，1984），并且已经在良性和恶性乳腺上皮细胞中证明了高水平的产生（Tokes等人，1981年）。在人类中，ACT的正常血清水平仅约为抗胰蛋白酶（AAT）的十分之一，并且这两种抑制剂都是急性期反应物。为了应对炎症或感染，ACT的血浆浓度增加至4倍这项工作得到了NIH Grant HL 27509的支持。JB是中国医学科学院基础医学研究所生物物理系休假期间获得世卫组织研究金的人。RNS是美国国立卫生研究院的博士后奖学金HL 07343的获得者。SLCW是霍华德休斯医学研究所的研究员，FDL是助理研究员。
Revised Manuscript Received June 12, 1987 abstract: arAntichymotrypsin belongs to a supergene family that includes «]-antitrypsin, antithrombin III, ovalbumin, and angiotensinogen. The human chromosomal arantichymotrypsin gene has been cloned and its molecular structure established. The gene is approximately 12 kb in length and contains five exons and four introns. The locations of the introns within the arantichymotrypsin gene are identical with those of the human arantitrypsin and angiotensinogen genes. Other members of this supergene family contain introns located at nonhomologous positions of the genes. The homologous organization of the aranti-chymotrypsin and arantitrypsin genes corresponds with the high degree of homology between their protein sequences and suggests that these loci arose by recent gene duplication. A model is presented for the evolution of both the genomic structure and the protein sequences of the serine protease inhibitor superfamily. arAntichymotrypsin (ACT) is a plasma serine protease inhibitor with affinity toward chymotrypsin-like enzymes (Travis et al., 1978a, b). Its target substrates include neu-trophile cathepsin G, mast cell chymase, and proteases that convert angiotensin I to the biologically active vasoconstrictor angiotensin II in vitro (Reilly et al., 1982; Wintroub et al., 1981; Tonnensen et al., 1982). It is a glycoprotein of 68000 daltons and is structurally related to arantitrypsin (AAT)(Morii & Travis, 1983a, b), which is a specific inhibitor of neutrophile elastase and protects the lung elastin fibers from degradation by this protease (Olsen et al., 1975; Tuttle & Jones, 1975). The physiological function of ACT has not been clearly defined. However, it has been shown that neutrophile cathepsin G enhances the rate of elastin digestion by neutro-phile elastase (Reilly & Travis, 1978) and that ACT is se-lectively concentrated in the bronchial lumen of patients with chronic infections (Ryley & Brogan, 1972). Thus, ACT could be involved in the maintenance of the overall protease-anti-protease balance in the lung. ACT has also been shown to markedly reduce the natural cytotoxic activityof T-cell killer lymphocytes (Graragha et al, 1982), presumably by binding to a chymotrypsin-like enzyme on the surface of these cells. In addition, it is a sensitive marker of hepatocellular carcinoma (Orodonez & Manning, 1984), and high-level production has been demonstrated in both benign and malignant breast ep-ithelial cells (Tokes et al., 1981). In man, the normal serum level of ACT is only about one-tenth thatof arantitrypsin (AAT), and both inhibitors are acute-phase reactants. In response to inflammation or infection, the plasma concentration of ACT increases to 4 times tThis work was supported by NIH Grant HL27509. JB is the recipient of a WHO fellowship on leave from the Department of Bio-physics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. RNS is a recipient of Postdoctoral Fellowship HL07343 from the National Institutes of Health. SLCW is an Investigator and FDL is an Assistant Investigator of the Howard Hughes Medical Institute.