Database: PubMedEntry: 6604220
Original site: 6604220
Owen MC, Brennan SO, Lewis JH, Carrell RW.
Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met
leads to Arg), a fatal bleeding disorder.
N Engl J Med. 1983 Sep 22;309(12):694-8.
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methionine at position 358 had been replaced by an arginine.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
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