Characterization of antithrombins produced by active site mutagenesis of human alpha 1-antitrypsin expressed in yeast |
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Authors: | George, PM Pemberton, P Bathurst, IC Carrell, RW Gibson, HL Rosenberg, S Hallewell, RA Barr, PJ |
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Affiliation: | Department of Pathology, Christchurch Hospital, New Zealand. |
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Abstract: | Both congenital and acquired antithrombin-III (AT-III) deficiencies are amenable to replacement therapy. We describe two antithrombins produced by recombinant DNA techniques from human alpha 1-antitrypsin (alpha 1AT) cDNA in yeast. Alteration of the alpha 1AT active site, replacing methionine 358 with arginine, results in a thrombin inhibition rate similar to that of heparin-activated AT-III. Alteration of two further residues, to give a five-residue sequence identical to AT-III, does not increase this rate further. Neither antithrombin is activated by heparin; both are unglycosylated and have shorter in vivo half-lives (t1/2) than human alpha 1AT. These antithrombins should be suitable for therapeutic replacement of AT-III in cases of congenital deficiency and in conditions associated with acquired AT-III deficiency, such as disseminated intravascular coagulation. |
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