Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blood coagulation factor V, the labile factor, is an important cofactor in the activation of prothrombin. Approximately 10 years ago, the first purification procedures for undegraded factor V from bovine and human plasma were reported. This was the starting point for a new area in the research on factor V structure-function relationships. In parallel to this, the structure of the even more labile anti-hemophilic factor (factor VIII) has been elucidated and the two proteins are found to be very similar in structure and in function. In this mini-review, I will focus on work performed in our laboratory, which has led forward to the proposal of a new structural model for factor V. It is based on results obtained with several different techniques, including protein chemistry, DNA technology and high resolution electron microscopy. In plasma, factor V circulates as a single chain, high molecular weight protein. During coagulation a limited number of peptide bonds are cleaved in the factor V molecule by thrombin. This leads to a great increase in biological activity. The active Va species is composed of a noncovalent complex between the N- and C-terminal fragments, whereas the activation fragments correspond to the carbohydrate-rich central portion of the molecule. The activity of factor Va is regulated through the selective degradation of the N-terminal heavy chain fragment by activated protein C. Purified human and bovine factor V was examined by high resolution transmission electron microscopy. Factor V was found to be composed of four major domains, three similar sized globular structures (diameter approx. 80 A) are linked via thin spacers to a larger central domain (diameter approx. 140 A). Activation with thrombin results in a reorganization of the molecule. The thrombin cleavage sites are positioned in the spacers between the different domains and two of the peripheral domains combine to form the active Va species. The new factor V model suggests that a unique and dramatic molecular reorganization occurs during the activation of factor V by thrombin and indicates that the low biological activity of single chain factor V is due to the physical separation of the N- and C-terminal domains by the large central region. Full biological activity can only be expressed after limited proteolysis by thrombin, when the two initially separated domains are free to combine to form the active factor Va molecule.
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PMID:A new model for coagulation factor V suggesting a unique mechanism of activation. 324 83

Resistance to activated protein C (APC) is associated with a single amino acid substitution in factor V (Arg506-->Gln, factor V Leiden) that results in delayed inactivation of the molecule by APC. The mutation is present in 20% of patients with a first episode of deep venous thrombosis. Arterial and venous thromboses are also associated with the type II protein C deficiency (protein CVermont). In protein CVermont, the substitution Glu20-->Ala alone (rPC gamma 20A) is responsible for the defective anticoagulant properties of PCVermont. It was recently established that a thrombotic episode occurred in 73% of family members who are heterozygous for both a functional protein C gene mutation and the factor V Leiden mutation. We evaluated the molecular defect that would accrue in the combined deficiency state of factor VR506Q/VaR506Q and rAPC gamma 20A using recombinant APC and natural purified factor VR506Q from patients homozygous for the Arg506-->Gln substitution. While wild-type recombinant APC (rAPC) slowly cleaves and inactivates factor VR506Q and factor VaR506Q, minimal cleavage of membrane-bound factor VR506Q and VaR506Q by rAPC gamma 20A at Arg306 and Arg679 occurs, and no loss in cofactor activity is observed. Our data demonstrate that rAPC gamma 20A cannot inactivate either factor VR506Q or factor VaR506Q at biologically relevant rates because of impaired cleavage at Arg306 and Arg679.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemical prototype for familial thrombosis. A study combining a functional protein C mutation and factor V Leiden. 748 40

The factor V Leiden variant, responsible for the phenomenon of activated protein C resistance, was found to be less frequent among British (0.06) and Swedish/Danish (0.15) protein C deficiency patients than previously reported in a Dutch study (0.19). In the Swedish population, a significantly increased frequency of the factor V Leiden allele was apparent in protein C deficiency patients as compared to healthy controls. However, this was not found in the British population. Coinheritance of the factor V Leiden variant is therefore unlikely to be the sole determinant of whether a person with protein C deficiency will come to clinical attention. Nevertheless, when patient data were analysed by type of protein C deficiency, it was noted that the frequency of the factor V Leiden variant was 2.8-fold higher in type II patients compared to type I patients. A possible explanation of this disparity is discussed.
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PMID:Population differences in the frequency of the factor V Leiden variant among people with clinically symptomatic protein C deficiency. 756 67

Inherited resistance to activated protein C (APC) was recently recognized as a novel cause underlying venous thrombophilia. In most cases APC-resistance is due to a single point mutation in the factor V gene leading to a replacement of Arg506 with Gln (factor V Leiden). Amino acid substitution occurs at one of the APC cleavage sites of factor Va, rendering it resistant to APC inactivation. Plasma anticoagulant response to exogenous APC as a simple diagnostic assay of APC- resistance shows good sensitivity and specificity as compared to gene analysis, yet standardization of the results needs to be improved. The APC-resistance trait is present in 2%-6% of the general population and was found to be associated with venous thrombophilia in about 20% of patients with unexplained thrombosis. Clinical features are substantially similar to other congenital plasma abnormalities predisposing to thrombosis (antithrombin III, protein C, protein S deficiencies); yet the overall clinical penetrance of the defect seems lower, at least for the heterozygous condition. Preliminary data suggest a higher risk of thrombosis in APC-resistant homozygous individuals or in patients exhibiting APC-resistance together with other thrombophilic genetic defects. To date, genetically determined APC-resistance does not seem to play a significant role in the development of arterial thrombotic disease.
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PMID:Resistance to activated protein C due to mutated factor V as a novel cause of inherited thrombophilia. 759 May 6

Resistance to activated protein C (APC) is the most common risk factor in venous thrombosis. A missense mutation in the factor V gene (factor V Leiden) is the molecular basis for this phenotype. Factor V Leiden was previously found in about 20% of unselected patients with thrombosis but also occurred in 3-5% of healthy Dutch controls. In the present study of Brazilian patients with venous thrombosis we also observed a frequency of 20% for this factor. In addition, in healthy Brazilian controls the frequency of the mutation was 2%. These data suggest that factor V Leiden has a similar distribution worldwide irrespective of the ethnic origin of the population.
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PMID:Factor V Leiden (FVQ 506) is common in a Brazilian population. 760 18

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.
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PMID:High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) 854 65

We investigated whether the occurrence of venous thrombosis in young women who use oral contraceptives might be explained by the factor V Leiden mutation, which leads to resistance to activated protein C and enhances susceptibility to thrombosis. We compared 155 consecutive premenopausal women, aged 15 to 49, who had developed deep venous thrombosis in the absence of other underlying diseases, with 169 population controls. The risk of thrombosis among users of oral contraceptives was increased 4-fold (relative risk 3.8 [95% CI 2.4-6.0]). The risk of thrombosis among carriers of the mutation compared with non-carriers was increased 8-fold (7.9 [3.2-19.4]). Compared with women who did not use oral contraceptives and were not carriers of the mutation, the risk of thrombosis among those with both risk factors was increased more than 30-fold (34.7 [7.8-154]). Recalculation of population incidences from these relative risks shows that the absolute risk of venous thrombosis in young women who use oral contraceptives is much larger when they carry the factor V Leiden mutation. When a young woman develops thrombosis, her factor V Leiden status should be considered in counselling about her future method of contraception.
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PMID:Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. 1456 59

Factor VIIIa is a non-covalent heterotrimer of A1, A2, and A3-C1-C2 subunits. Previously, we speculated that the central portion of the A2 subunit, in and around the activated protein C-sensitive bond at Arg562-Gly (Fay, P. J., Smudzin, T.M., and Walker, F.J. (1991) J. Biol. Chem. 266, 20139-20145), is important for macromolecular interactions within the factor Xase enzyme complex. A peptide corresponding to factor VIII residues 558-565, SVDQRGNQ and designated FVIII558-565, was chemically synthesized and inhibited factor Xa generation in a purified system with an apparent KI of 105 microM. Tryptic cleavage of FVIII558-565 eliminated its inhibitory activity, whereas a scrambled sequence version of the peptide possessed < 30% the inhibitory activity of the native version. Overlapping peptides FVIII556-564 and FVIII561-569 were also inhibitory and confirmed the importance of residues in and around the scissile bond for functional factor Xase. Kinetic analysis revealed that peptide-mediated inhibition was non-competitive with respect to factor X. However, increasing factor IXa concentration overcame the observed inhibition. Furthermore, the peptide inhibited the factor IXa-dependent enhancement of factor VIIIa reconstituted from isolated A1/A3-C1-C2 dimer plus A2 subunit. Isolated factor VIII heavy chain (contiguous A1-A2 domains) was cleaved at Arg336 by an equimolar concentration of factor IXa in a reaction that was phospholipid-independent. No proteolysis of the isolated A1 subunit was observed in a similar reaction. These results indicate that the A2 subunit sequence delineated by residues 558-565 contributes to the interaction of cofactor with protease and that this interaction is essential for intrinsic factor Xase activity. Furthermore, that this peptide blocks both factor Xase activity and the capacity of factor IXa to stabilize the labile factor VIIIa heterotrimer suggest that this latter property is of physiologic significance.
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PMID:Factor VIIIa A2 subunit residues 558-565 represent a factor IXa interactive site. 805 Nov 50

Antiphospholipid syndrome is associated with venous, arterial, and placental thrombosis, possibly through autoantibody impairment of phospholipid-dependent protein C activation. Recently, a missense mutation in the factor V gene (1691 G-->A) has been identified that results in an abnormal factor V product (1). This mutation, known as the Leiden mutation, causes an amino acid substitution of glutamine for arginine at position 506 in the factor V molecule and renders the protein resistant to proteolytic inactivation by activated protein C and thus predisposes to thrombosis (2, 3). We hypothesized that some individuals with antiphospholipid syndrome may also carry the Leiden mutation, and thus have a "second hit" predisposition to thrombosis. To test this hypothesis, allele-specific hybridization and allele-specific restriction analysis were used to test for the Leiden mutation in thirty women with the antiphospholipid syndrome, 10 of whom had a history of thrombosis. None of the women were heterozygous or homozygous for the factor V mutation. We conclude that the presence of the factor V Leiden mutation is not a prerequisite for the thrombotic events in patients with antiphospholipid syndrome, due to the occurrence of thrombosis seen in patients lacking the factor V mutation.
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PMID:The factor V Leiden mutation which predisposes to thrombosis is not common in patients with antiphospholipid syndrome. 856 Apr 6

The recent discovery of the factor V Leiden mutation as the molecular defect in the large majority of APC-resistant individuals, has drastically changed our view on familial thrombophilia and it has contributed to a better understanding of the interaction of genetic and environmental risk factors. It has offered firm support for the view that venous thrombosis is a multifactorial disease and that the risk of thrombosis will increase as the number of genetic and/or environmental risk factors increases.
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PMID:Resistance to activated protein C and factor V Leiden as risk factors for venous thrombosis. 857 4


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