ArticleThe Biochemical journal2004
Augmented intrinsic activity of Factor VIIa by replacement of residues 305, 314, 337 and 374: evidence of two unique mutational mechanisms of activity enhancement.
Article in The Biochemical journal, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 45 citations in OpenAlex.
- A systematic approach for evaluating the role of surface-exposed loops in trypsin-like serine proteases applied to the 170 loop in coagulation factor VIIa.Scientific reports · 2022Article
- Beating tissue factor at its own game: Design and properties of a soluble tissue factor-independent coagulation factor VIIa.The Journal of biological chemistry · 2020Article
- Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.Molecular therapy. Methods & clinical development · 2019Review
- Molecular Basis of Enhanced Activity in Factor VIIa-Trypsin Variants Conveys Insights into Tissue Factor-mediated Allosteric Regulation of Factor VIIa Activity.The Journal of biological chemistry · 2016Article
- The effects of 2-chloroprocaine on coagulation and fibrinolysis in the parturient: an in vitro study.Journal of anesthesia · 2014Article
- Enhancing human spermine synthase activity by engineered mutations.PLoS computational biology · 2013Article
- Structural biology of factor VIIa/tissue factor initiated coagulation.Frontiers in bioscience (Landmark edition) · 2012Review
- Antibody-induced enhancement of factor VIIa activity through distinct allosteric pathways.The Journal of biological chemistry · 2012Article
- Recombinant factor VIIa analog NN1731 (V158D/E296V/M298Q-FVIIa) enhances fibrin formation, structure and stability in lipidated hemophilic plasma.Thrombosis research · 2011Article
- Article
- Analysis of factor VIIa binding to relipidated tissue factor by surface plasmon resonance.Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis · 2010Article
- Long-term expression of canine FVIIa in hemophilic dogs.Thrombosis research · 2010Review
- Mechanism of the Ca2+-induced enhancement of the intrinsic factor VIIa activity.The Journal of biological chemistry · 2008Article
- A combined structural dynamics approach identifies a putative switch in factor VIIa employed by tissue factor to initiate blood coagulation.Protein science : a publication of the Protein Society · 2007Article
- Disulfide locked variants of factor VIIa with a restricted beta-strand conformation have enhanced enzymatic activity.Protein science : a publication of the Protein Society · 2005Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Coagulation Factor VIIa (FVIIa) lacks the ability to spontaneously complete the conversion to a fully active enzyme after specific cleavage of an internal peptide bond (Arg152-Ile153) in the zymogen. Recently, several variants of FVIIa with enhanced intrinsic activity have been constructed. The in vitro characterization of these variants has shed light on molecular determinants that put restrictions on FVIIa in favour of a zymogen-like conformation and warrants continued efforts. Here we describe a new FVIIa variant with high intrinsic activity containing the mutations Leu305-->Val, Ser314-->Glu, Lys337-->Ala, and Phe374-->Tyr. The variant, called FVIIa(VEAY), processes a tripeptidyl substrate very efficiently because of an unprecedented, 5.5-fold lowering of the K(m) value. Together with a 4-fold higher substrate turnover rate this gives the variant a catalytic efficiency 22 times that of wild-type FVIIa, which is reflected in a considerably enhanced susceptibility to inhibition by antithrombin and other inhibitors. For instance, the affinity of FVIIa(VEAY) for the S1 probe and inhibitor p -aminobenzamidine is represented by an 8-fold lower K(i) value compared with that of FVIIa. Activation of Factor X in solution occurs about 10 times faster with FVIIa(VEAY) than with FVIIa, due virtually exclusively to an increased kcat value. The high activity of FVIIa(VEAY) is not accompanied by an increased burial of the N-terminus of the protease domain. A comparison of the kinetic parameters and molecular properties of FVIIa(VEAY) with those of the previously described mutant V158D/E296V/M298Q-FVIIa (FVIIa(IIa)), and the locations of the substitutions in the two variants, reveals what appear to be two profoundly different structural mechanisms dictating improvements in enzymic performance.
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