An Arg/Ser substitution in the second epidermal growth factor-like module of factor IX introduces an O-linked carbohydrate and markedly impairs activation by factor XIa and factor VIIa/Tissue factor and catalytic efficiency of factor IXa.
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Hertzberg MS, Facey SL, Hogg PJ
An Arg/Ser substitution in the second epidermal growth factor-like module of factor IX introduces an O-linked carbohydrate and markedly impairs activation by factor XIa and factor VIIa/Tissue factor and catalytic efficiency of factor IXa.
Blood. 1999 Jul 1;94(1):156-63.
- PubMed ID
- 10381508 [ View in PubMed]
- Abstract
Factor IXR94S is a naturally occurring hemophilia B defect, which results from an Arg 94 to Ser mutation in the second epidermal growth factor (EGF)-like module of factor IX. Recombinant factor IXR94S was activated by factor XIa/calcium with an approximately 50-fold reduced rate and by factor VIIa/tissue factor/phospholipid/calcium with an approximately 20-fold reduced rate compared with wild-type factor IX. The apparent molecular mass of the light chain of factor IXaR94S was approximately 6 kD higher than that of plasma or wild-type factor IX, which was not corrected by N-glycosidase F digestion. This result indicated the presence of additional O-linked carbohydrate in the mutant light chain, probably at new Ser 94. The initial rate of activation of factor X by factor IXaR94S in the presence of polylysine was 7% +/- 1% of the initial rate of activation of factor X by plasma factor IXa, and the kc/Km for activation of factor X by factor IXaR94S/factor VIIIa/phospholipid/calcium was 4% +/- 1% of the kc/Km for activation of factor X by plasma factor IXa/factor VIIIa/phospholipid/calcium. The reduced efficiency of activation of factor X by factor IXaR94S in the tenase enzyme complex was due to a 58-fold +/- 12-fold decrease in kcat with little effect on Km. In conclusion, the R94S mutation had introduced an O-linked carbohydrate, which markedly impaired both activation by factor XIa and turnover of factor X in the tenase enzyme complex.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Coagulation Factor IX (Recombinant) Coagulation factor VII Protein Humans YesLigandDetails Coagulation Factor IX Human Coagulation factor VII Protein Humans YesLigandDetails