Characterization of antithrombins produced by active site mutagenesis of human alpha 1-antitrypsin expressed in yeast
| Autor: | H L Gibson, RW Carrell, P Pemberton, IC Bathurst, Peter M. George, S Rosenberg, PJ Barr, RA Hallewell |
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| Rok vydání: | 1989 |
| Předmět: |
Immunology
Molecular Sequence Data Alpha (ethology) Saccharomyces cerevisiae Biology Biochemistry Antithrombins law.invention chemistry.chemical_compound Thrombin Drug Stability law Complementary DNA Sequence Homology Nucleic Acid medicine Humans Amino Acid Sequence Methionine Binding Sites Base Sequence Antithrombin Mutagenesis Genetic Variation Cell Biology Hematology Molecular biology Recombinant Proteins Kinetics chemistry alpha 1-Antitrypsin Mutation Recombinant DNA medicine.drug |
| Zdroj: | Blood. 73(2) |
| ISSN: | 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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