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

Gamma-carboxyglutamic acid is an amino acid with a dicarboxylic acid side chain. This amino acid, with unique metal binding properties, confers metal binding character to the proteins into which it is incorporated. This amino acid has been discovered in blood coagulation proteins (prothrombin, Factor X, Factor IX, and Factor VII), plasma proteins of unknown function (Protein C, Protein S, and Protein Z), and proteins from calcified tissue (osteocalcin and bone-Gla protein). It has also been observed in renal calculi, atherosclerotic plaque, and the egg chorioallantoic membrane, among other tissues. Gamma-carboxyglutamic acid is synthesized by the post-translational modification of glutamic acid residues. This reaction, catalyzed by a hepatic carboxylase, requires reduced vitamin K, oxygen, and carbon dioxide. The function of gamma-carboxyglutamic acid is uncertain. In prothrombin gamma-carboxyglutamic acid residues bound to metal ions participate as an intramolecular non-covalent bridge to maintain protein conformation. Additionally, these amino acids participate in the calcium-dependent molecular assembly of proteins on membrane surfaces through intermolecular bridges involving gamma-carboxyglutamic acid and metal ions.
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PMID:Gamma-carboxyglutamic acid. 645 61

An infant with recurrent purpura fulminans in the first year of life was found to have severe homozygous deficiency of protein C (less than 1% of normal levels). The episodes of purpura fulminans were controlled by infusions of fresh frozen plasma containing protein C. The requirement of frequent plasma infusions, however, eventually resulted in several complications secondary to hyperproteinemia. Factor IX concentrates rich in protein C were then given to maintain adequate levels of the factor while minimizing the amount of extraneous proteins. The patient has remained asymptomatic and free of complications for greater than 10 months while receiving these concentrates every 48 hours.
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PMID:Severe homozygous protein C deficiency. 654 78

Previous work has shown that two vitamin K-dependent plasma zymogens, factor X and protein C, each contain one residue of erythro-beta-hydroxyaspartic acid. In the present study, prothrombin, factor VII and factor IX were subjected to amino acid analyses for beta-hydroxyaspartic acid. Factor IX and factor VII each contain one residue of erythro-beta-hydroxyaspartic acid. Edman sequence analyses revealed that this residue occurs at position 64 in human and bovine factor IX. Inasmuch as the nucleotide sequence codes for aspartic acid at this position, it appears highly likely that beta-hydroxyaspartic acid is formed in these proteins by a post-translational hydroxylation of aspartic acid. In contrast, neither human nor bovine prothrombin contain beta-hydroxyaspartic acid.
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PMID:The occurrence of beta-hydroxyaspartic acid in the vitamin K-dependent blood coagulation zymogens. 668 26

In the last few years, plasma fractionation has been subjected to major technological changes which have contributed to improve the viral safety and overall purity of plasma derivatives. New viral inactivation treatments, primarily solvent-detergent and pasteurization, have been introduced in the manufacturing processes of plasma derivatives to ensure the inactivation of major plasma-borne viruses, including HIV and hepatitis B and C viruses. Concurrently, new highly purified products obtained by chromatographic methods (mainly ion exchange and/or immunopurification) have been developed in the last five years and have replaced former preparations, providing a significantly higher safety level in terms of purity and viral risks. For an example, the new generation of Factor VIII and Factor IX concentrates (to treat hemophilia A and hemophilia B, respectively), which have been introduced in the last five years, are purified over 10,000- to 20,000-fold from plasma, as compared to only 50- to 100-fold for the former products. Similarly, new, standardized, clotting factor or protease inhibitor concentrates have been made available, thus permitting to carry out selective hemotherapy of specific diseases. Examples include the development of von Willebrand factor, factor XI, protein C, or alpha 1-antitrypsin concentrates for the substitutive therapy of congenital or acquired deficiencies. In addition, the concept of good manufacturing practices has been implemented, whereas carefully controlled, validated processes are contributing to the consistency in the quality of those products. Current major problems in plasma fractionation relate to the potential occurrence of new pathogenic agents that could resist present viral inactivation treatments and to the potential effect of given purification technologies on the development of immunogenic properties of proteins. Current trends indicate that significant progress in viral safety of plasma derivatives (for example through the introduction of new concept such as viral filtration) are to be expected very soon. Further research in this very important field is mandatory as plasma should remain the starting material of important therapeutic products in the coming years.
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PMID:[Plasma fractionation. Progress, problems and perspectives]. 799 59

The purified factor IX concentrates Nanotiv (Kabi Pharmacia), Immunine (Immuno), Factor IX VHP (Bio-transfusion), Alphanine (Alpha) and Mononine (Armour) have been studied in vitro and compared with the prothrombin complex concentrates (PCCs) Preconativ (Kabi Pharmacia) and Prothromplex TIM4 (Immuno). The measured values for factor IX coagulant activity (IX:C) were in good agreement with the manufacturer's label values. In contrast to the PCCs, most of the purified concentrates were virtually devoid of other vitamin K-dependent coagulation factors, the inhibitors protein C and S as well as fibrinogen, fibronectin and immunoglobulins. Indicators of thrombin generation, namely prothrombin fragments 1 and 2 (F 1 + 2) and thrombin-antithrombin complex (TAT), were present in varying amounts in all preparations. The specific activity in the purified concentrates exceeded that in the PCCs by a factor of 50-100. Some differences in purity were found between the purified concentrates. In vivo, Nanotiv was compared with Preconativ and Immunine with Prothromplex TIM4 in crossover studies in patients with severe hemophilia B, and Mononine was tested in a single drug study. Most of the preparations yielded postinfusion increases in TAT, but not in F 1 + 2. Pharmacokinetic variables were analyzed with non-linear curve-fitting combined with model-independent methods. In retrospective comparisons, there were no apparent differences between Nanotiv, Preconativ and Mononine, whereas in vivo recovery seemed lower and the apparent clearance higher for Immunine and Prothromplex. Purified factor IX concentrates were successfully used as cover for surgery or in immune tolerance induction.
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PMID:Biochemical and in vivo properties of high purity factor IX concentrates. 812 33

Factor IX consists of a gamma-carboxyglutamic acid-rich domain followed by two epidermal growth factor (EGF)-like domains and the C-terminal protease domain. To delineate the function of EGF1 domain in factor IX, we constructed three mutants: an EGF1 domain-deleted mutant (IX delta EGF1), a point mutant (IXQ50P) with a Gln-50-->Pro change, and a replacement mutant (IXPCEGF1) in which the EGF1 domain of factor IX was replaced by that of protein C. These mutants and wild-type (WT) factor IX (IXWT) were expressed in 293 kidney cells by using pRc/CMV vector. The purified proteins had the same gamma-carboxyglutamic acid content as the normal plasma factor IX (IXNP) and were activated normally by factor XIa-Ca2+. In contrast, IX delta EGF1 could not be activated by factor VIIa-tissue factor-Ca2+, and the activation of IXPCEGF1 in this system was markedly slow; however, IXQ50P was activated at a normal rate. In additional studies, both IXWT and IX delta EGF1 were rapidly converted to their respective IX alpha forms by factor Xa-phospholipid-Ca2+. Since this reaction has an absolute requirement for phospholipid, it indicates that the mutants under study are not impaired in their interactions with phospholipid. Relative coagulant activities of factor XIa-activated proteins were IXNP, 100%; IXWT, 75-85%; IX delta EGF1, < or = 1%; IXPCEGF1, < or = 2%; and IXQ50P, 6-10%. We conclude that the EGF1 domain of factor IX is required for its activation by factor VIIa-tissue factor and that the Gln-50 residue is not critical for this activation. Further, the EGF1 domain of factor IX is not essential for phospholipid binding and for its activation by factor XIa. In addition, the low coagulant activities of the activated mutants indicate that the EGF1 domain is also important in factor X activation by factor IXa-factor VIIIa-Ca(2+)-phospholipid complex.
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PMID:First epidermal growth factor-like domain of human blood coagulation factor IX is required for its activation by factor VIIa/tissue factor but not by factor XIa. 817 Sep 49

The carbohydrate-deficient glycoprotein (CDG) syndromes are a newly recognized group of inherited metabolic diseases. We report a Japanese brother and sister with a CDG syndrome. Both patients showed decreased activities of blood coagulation Factor XI and of the coagulation inhibitor protein C. In one of them there was also a somewhat decreased activity of Factor IX and of antithrombin III. Isoelectric focusing of antithrombin III revealed a decrease of negatively charged fractions and an increase of more cathodal bands. Furthermore, there was a discrepancy between activity and antigen level of Factor VIII and protein C. The patients had an incidental deficiency of factor XII. This is the first detailed report on blood coagulation systems in the CDG syndromes. These blood coagulation abnormalities may explain at least in part the thrombotic or haemorrhagic complications of the CDG syndromes.
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PMID:Decreased blood coagulation activities in carbohydrate-deficient glycoprotein syndrome. 841 4

The vitamin-K-dependent serine proteinases of coagulation have evolved by a process of gene duplication and divergence, acquiring along the way a considerable degree of functional diversity that has equipped them for their different roles in haemostasis. The cDNA sequences encoding the catalytic domains of the early mammalian ancestors of five vitamin-K-dependent factors (factors VII, IX and X, protein C and prothrombin) were reconstructed by employing cDNA sequence data from a range of extant mammals and by using established phylogenies. The cDNA sequence of the putative common ancestor of these early mammalian proteins was then reconstructed from the five sequences by using a deduced phylogeny that was different in a number of respects from those previously proposed. Factor IX is proposed to have branched off early on, followed by protein C and prothrombin and finally factors VII and X. Significant differences in mutation rates were observed between proteins within a species; factor IX exhibited a lower mutation rate than the other proteins, consistent with its early emergence. Differences in mutation rates were also observed between species for a given protein and these exhibited an inverse correlation with generation time. A biophysically plausible structure for the ancestral vitamin-K-dependent factor protein was constructed by comparative methods. Studies of the functional architecture of this model provide new insights into the evolution of protein-binding specificity in this family of proteins.
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PMID:Molecular reconstruction and homology modelling of the catalytic domain of the common ancestor of the haemostatic vitamin-K-dependent serine proteinases. 870 9

Carbohydrate-deficient glycoprotein (CDG) syndrome type I is an autosomal recessive disease with multisystemic manifestations. During childhood the patients may suffer from hemorrhages, which may be lethal, venous thromboses and stroke-like episodes. In this study 15 patients with CDG syndrome type I were examined from the levels and isoform patterns of coagulation factors and inhibitors and fibrinolysis parameters. The screening assays APTT and PTC were unaffected in most cases. In spite of this reduced levels were found particularly for factors II, V, X and XI and for antithrombin and protein C. Low values tended to be associated with elevated liver enzyme levels in serum. The values were at potential clinical risk levels for protein C and/or antithrombin in more than half of the patients, and for factor V and/or factor XI in one third of them. There were no current differences in values between patients who had previously displayed clinical symptoms of coagulation disturbance and those without such symptoms. Partially carbohydrate-deficient isoforms were demonstrated in antithrombin, protein C, protein S and in alpha 2-antiplasmin, but not in factors II, X and fibrinogen. Abnormal isoforms did not appear to reduce the functional activity of the respective glycoproteins. Analysis of individual hemostatic parameters is recommended in these patients in connection with clinical symptoms or elective surgery. The observed variability of the carbohydrate defect in glycoproteins in this disease may be a clue to its pathogenesis.
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PMID:Complex functional and structural coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome type I. 873

Factor IX is a factor of the blood coagulation system. Its activation occurs on the surface of phospholipid membranes. It can be activated by the factor VIIa-TF (tissue factor)-Ca2+ complex via an extrinsic pathway and by factor XIa in the presence of Ca2+ via the intrinsic pathway of blood coagulation system activation. The activated factor IXa is a serine proteinase. The main function of the activated factor IXa in complex with factor VIIIa and phospholipids in presence of Ca2+ consists of the activation of factor X. Factor IX is synthesized in the liver and is subject to a number of posttranslational modifications including gamma-carboxylation, beta-hydroxylation, and glycosylation. It forms a subgroup of vitamin K-dependent plasma proteins including factors VII and X and protein C characterized by identical domain structures having high levels of homology. Factor IX consists of an NH2-terminal Gla domain, two epidermal growth factor (EGF)-like domains, and a C-terminal domain containing Ser in its active site. Factor IX deficiency in human plasma results in the disease known as hemophilia B.
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PMID:Factor IX of the blood coagulation system: a review. 933 59


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