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Antithrombin Budapest 3 An antithrombin variant with reduced heparin affinity resulting from the substitution L99F
Author(s) -
Olds R.J.,
Lane D.A.,
Boisclair M.,
Sas G.,
Bock S.C.,
Thein S.L.
Publication year - 1992
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(92)80854-a
Subject(s) - antithrombin , heparin , substitution (logic) , chemistry , biochemistry , pharmacology , medicine , computer science , programming language
The molecular basis and functional properties of a variant antithrombin (AT) protein. AT Budapest 3, were studied. A single base substitution was identified in codon 99, TC→ TC, altering the normal leucine to phenylalanine. The proband presented with a history of venous thrombotic disease and was found to be homozygous for the mutation. The variant protein demonstrated reduced heparin affinity and reduced antiproteinase activity in the presence of either unfractionated heparin or the AT‐binding heparin pentasaccharide, when compared to normal AT. A small change in the isoelectric point was also identified. The substituted amino acid residue of AT Budapest 3 is located near to the proposed AT heparin binding site, and it is suggested that reduced heparin affinity of the variant protein may result from substitution‐induced distortion of positive charge geometry in the binding site and/or changes in its position relative to the rest of the inhibitor molecule.