Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder.
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 A variant alpha 1-antitrypsin was identified in which the methionine at position 358 had been replaced by an arginine.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.
D000293:Adolescent; D000595:Amino Acid Sequence; D000990:Antithrombin III / Q000032:analysis / Q000235:genetics*; D001120:Arginine / Q000032:analysis; D014644:Genetic Variation; D006474:Hemorrhagic Disorders / Q000201:enzymology* / Q000628:therapy; D006801:Humans; D008297:Male; D008715:Methionine / Q000032:analysis; D009154:Mutation; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D010951:Plasma Exchange; D014947:Wounds and Injuries / Q000150:complications; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000235:genetics*
D000515:alpha 1-Antitrypsin; C038915:alpha 1-antitrypsin Pittsburgh; D000990:Antithrombin III; D001120:Arginine; D008715:Methionine; D010196:Pancreatic Elastase