Owen M C, Brennan S O, Lewis J H, Carrell R W
N Engl J Med. 1983 Sep 22;309(12):694-8. doi: 10.1056/NEJM198309223091203.
Our previous studies predicted a functional relationship between the plasma proteins alpha 1-antitrypsin and antithrombin III. To elucidate this relationship we investigated the plasma of a 14-year-old boy who had died from an episodic bleeding disorder. A variant alpha 1-antitrypsin was identified in which the methionine at position 358 had been replaced by an arginine. This had converted the alpha 1-antitrypsin from its normal function as an inhibitor of elastase to that of an inhibitor of thrombin. This finding indicates that the reactive center of alpha 1-antitrypsin is methionine 358, which acts as a bait for elastase, just as the normal reactive center of antithrombin III is arginine 393, which acts as a bait for thrombin. The independence of the new thrombin inhibitor from heparin control explains the bleeding disorder; it also indicates that heparin normally acts directly on antithrombin III, revealing its inherent inhibitory activity. The episodic nature of the bleeding was a consequence of the mutant protein's being an acute-phase reactant, the level of which increased several-fold after trauma.
我们之前的研究预测血浆蛋白α1-抗胰蛋白酶和抗凝血酶III之间存在功能关系。为了阐明这种关系，我们研究了一名死于发作性出血性疾病的14岁男孩的血浆。鉴定出一种变异的α1-抗胰蛋白酶，其中第358位的甲硫氨酸被精氨酸取代。这使得α1-抗胰蛋白酶从其作为弹性蛋白酶抑制剂的正常功能转变为凝血酶抑制剂的功能。这一发现表明α1-抗胰蛋白酶的反应中心是甲硫氨酸358，它作为弹性蛋白酶的诱饵，就像抗凝血酶III的正常反应中心是精氨酸393，作为凝血酶的诱饵一样。新的凝血酶抑制剂不受肝素控制，这解释了出血性疾病；这也表明肝素通常直接作用于抗凝血酶III，揭示其固有的抑制活性。出血的发作性是突变蛋白作为急性期反应物的结果，其水平在创伤后会增加几倍。
