Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein C is a vitamin K-dependent plasma serine protease zymogen, which upon activation, functions as an anticoagulant. Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM). This activation is Ca(2+)-dependent, but Ca2+ inhibits protein C activation by thrombin alone. In most proteases, specificity is determined primarily by the residues that lie near the scissile bond. In protein C, the P2 position is Pro, whereas in the fibrinogen A chain, P2 is Val. We have expressed a Pro-->Val mutant of protein C (P168V) in mammalian cells. At saturating Ca2+, the P168V and wild-type proteins were activated by the T-TM complex equivalently, but half maximal rates of activation were obtained at 50 mumol/L Ca2+ for wild type and approximately 5 mmol/L Ca2+ for the P168V mutant. In the absence of TM, Ca2+ no longer inhibited the activation of the P168V mutant. These results indicate that Pro168 influences the Ca(2+)-dependent conformational changes in protein C that control activation. Recently, a patient with thrombotic complications has been identified with a Pro168-->Leu substitution. Both the P168V and the P168L mutation lead to impaired secretion caused by retention within the cell.
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PMID:Proline at the P2 position in protein C is important for calcium-mediated regulation of protein C activation and secretion. 816 37

In 15 patients with systemic sclerosis (SS) and 8 patients suffering from silicosis and/or silica dust exposure-associated scleroderma (SAS), various parameters of endothelial cell and platelet function and of blood coagulation and fibrinolysis were studied. In 9 of the 23 patients the values for the von Willebrand factor antigen were increased, and the same applied to the endothelin levels in 8 of 23 patients. Protein C, protein S, anti-thrombin III and tissue plasminogen activator (before and after 10 min venous occlusion) were normal. The plasminogen activator inhibitor, however, was increased in 5 patients. Increased levels of platelet factor 4 and of beta-thromboglobulin were found in 20 patients, while the ADP- and epinephrine-induced platelet aggregation was reduced in 5 patients. No individual patient was found to have a general disturbance of all parameters. The deviations in the parameters of endothelial cell and platelet function and of blood coagulation and fibrinolysis proved to be rather inconsistent. This suggests different functional stages in dependence on the various influential factors. There was no close correlation either with the severity of Raynaud's phenomenon or with the type of SS. In addition, there were no basic differences between SS and SAS. The disturbances occurred with similar frequency and in similar proportions in both disease groups.
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PMID:[Vascular function parameters in idiopathic and quartz-induced progressive scleroderma]. 827 90

Proteins C and S are vitamin K-dependent proteins with an essential anti-coagulant function. Protein C exists in an inactive form and is activated by a thrombin-thrombomodulin complex. Protein S combines with protein C and forms a stoichiometric complex which regulates coagulation in the presence of calcium. As patients with sickle cell disease (SCD) bear a high risk of developing thrombo-embolic disorders, we studied the coagulation derangement in 100 patients and 40 normal age- and sex-matched controls. The patients were clinically assessed and classified into sickle cell homozygotes (Hb SS), Hb S heterozygotes (Hb AS) and double heterozygotes for Hb S/beta 0-thalassaemia based on haematological parameters, red cell indices, Hb A2 and F levels and genetic studies. The proteins C and S were estimated and related to the type of the gene defect. The results showed significantly reduced levels of proteins C and S in SCD patients with the highest prevalence of deficiency in patients with a severe disease and frequent episodes of crisis. However, no significant differences were encountered in the level of proteins C and S in the same patients during the steady state and during episodes of crisis. It was concluded that the lower protein C and S levels in SCD is either due to decreased production or increased consumption though this reduction does not seem to play a role in producing thrombo-embolic disorders.
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PMID:Blood proteins C and S in sickle cell disease. 829 68

An Italian family with a dysfunctional protein C (type II deficiency) tentatively designated Protein C Padua has been investigated. Five family members had this defect. Thrombotic manifestations occurred in the propositus, his sister, and his 87-year-old mother, who suffered from a transitory ischemic attack (TIA). All other deficient patients were asymptomatic. The abnormality was consistent with normal protein C (PC) antigen level but reduced both anticoagulant and amidolytic activities after PC activation by Protac. When thrombin was used as activator, PC activity level was also reduced. The abnormal PC molecule seemed to have a defect involving the activation region or the active site mechanism (reduced activity level regardless of the PC activators and the methods used in the functional assays). The electrophoretic mobility of the dysfunctional protein, assayed by crossed-immunoelectrophoresis (CIE), was normal in presence of both Na citrate and calcium lactate. The kinetics of antigen-antibody complex formation between the abnormal PC and anti-PC polyclonal antibody was investigated by means of a laser nephelometer and a peculiar pattern was found in the affected patients suggesting a possible anomalous interaction between the antibody and the abnormal protein.
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PMID:A family with an abnormal protein C and a thrombotic tendency. 833 96

Protein C (PC) is an anticoagulant protein which, being activated by thrombin, degrades factors V/Va and VIII/VIIIa and releases a tissue-type plasminogen activator. Some Agkistrodon snake venoms contain PC activators which, in experiments, exert an anticoagulant action. An antithrombotic effect of the PC activator from the venom of A. blomhoffi ussuriensis on the model of thrombus formation in the arterio-venous shunt in rats was under investigation. Administration of the PC activator resulted in a dose-dependent prolongation of the thrombus formation time and a decrease in plasma PC activity, which were accompanied by a decrease in factor V activity and APTT prolongation. No reliable changes in the t-PA level, ADP- and epinephrine-induced platelet aggregation were observed. Platelet adhesion to glass beads diminished. We assume that the antithrombotic effect of the PC activator from the A. blomhoffi venom in the platelet-dependent thrombosis model is caused by PC activation and subsequent factor V inactivation as well as by platelet adhesiveness reduction.
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PMID:Protein C activator from the venom of Agkistrodon blomhoffi ussuriensis retards thrombus formation in the arterio-venous shunt in rats. 837 94

When amino acids Pro60B, Pro60C, and Trp60D are deleted from thrombin, the resulting mutant (des-PPW) exhibits (compared to the wild-type enzyme): a similar second order rate constant of inhibition (k(on)) for diisopropyl fluorophosphate, and a comparable inhibition constant (K(i)) for benzamidine, suggesting that the charge stabilizing system and the primary binding pocket are little altered, if at all, by the mutation. As predicted from the x-ray structure, des-PPW is remarkably sensitive to the bovine pancreatic trypsin inhibitor, with a K(i) over 3 x 10(3) times tighter relative to thrombin, but des-PPW is also markedly less susceptible to inactivation by antithrombin III, with a k(on) that is over 100-fold lower. The catalytic constant (kcat) for most p-nitroanilide substrates tested is preserved or even increased, but the Michaelis constant (Km) increases. In contrast, the Km for the fibrinogen A alpha-chain is essentially unchanged, whereas kcat decreases approximately 50-fold. Unlike thrombin, the rate of fibrinopeptide B release becomes, following a lag phase, comparable to that of fibrinopeptide A. Inasmuch as des-PPW cleaves an additional peptide bond in the bovine fibrin alpha-chain, it remains a highly specific serine protease, which releases a single peptide from denatured casein (versus two with thrombin). Protein C activation by des-PPW is approximately 30 times slower than by thrombin in the absence, as well as in the presence, of calcium and thrombomodulin. Although this study confirms that the B-insertion restricts access to the active site cleft, it also suggests that other motifs and/or discrete amino acids are mainly responsible for the narrow specificity of thrombin.
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PMID:The role of thrombin's Tyr-Pro-Pro-Trp motif in the interaction with fibrinogen, thrombomodulin, protein C, antithrombin III, and the Kunitz inhibitors. 839 26

Blood coagulation abnormalities induced by administration of E. coli L-asparaginase were investigated in 25 patients with acute lymphoblastic leukemia treated according to the GIMEMA ALL 0288 trial. Dosage of L-asparaginase was relatively low (6,000 U/m2/day for 7 days total dose 42,000 U/m2) as compared to the conventional dosages (120,000-140,000 U/m2 over 10-14 days). A significant decrease in fibronogen, plasminogen, alpha2-antiplasmin and antithrombin III was observed from day IV of L-asparaginase and it was maximum on day VIII, with return to the baseline levels on day XV. Protein C levels had only a borderline reduction, while no modification of protein S or factor VII was observed. Two of the patients investigated developed thrombosis. The presence of a prothrombotic state induced even by this low dosage of E. coli L-asparaginase was suggested by a significant increase of sensitive markers of hypercoagulability such as fibrinopeptide A, thrombin-antithrombin complexes, and prothrombin fragment F1 + 2.
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PMID:Evidence of a hypercoagulable state in patients with acute lymphoblastic leukemia treated with low dose of E. coli L-asparaginase: a GIMEMA study. 844 31

The wealth of structural information now available for thrombin, its precursors, its substrates, and its inhibitors allows a rationalization of its many roles. alpha-thrombin is a rather rigid molecule, binding to its target molecules with little conformational change. Comparison of alpha-thrombin with related trypsin-like serine proteinases reveals an unusually deep and narrow active site cleft, formed by loop insertions characteristic of thrombin. This canyon structure is one of the prime causes for the narrow specificity of thrombin. The observed modularity of thrombin allows a diversity in this specificity; its "mix-and-match" nature is exemplified by its interactions with macromolecules (Fig. 20). The apposition of the active site to a hydrophobic pocket (the apolar binding site) on one side and a basic patch (the fibrinogen recognition exosite) on the other allows for a fine tuning of enzymatic activity, as seen for fibrinogen. Thrombin receptor appears to use the same sites, but in a different way. Protein C seems only able to interact with thrombin if the recognition exosite is occupied by thrombomodulin. These two sites are also optimally used by hirudin, allowing the very tight binding observed; thrombin inhibition is effected by blocking access to the active site. On the other hand, antithrombin III makes little use of the recognition exosite; instead, its interactions are tightened with the help of heparin, which binds to a second basic site (the heparin binding site). Thrombin's modularity is a result of the conjunction of amino acid residues of like properties, such as charge or hydrophobicity. The charge distribution plays a role, not only in the binding of oppositely charged moieties of interacting molecules, but also in selection and preorientation of them. Nonproteolytic cellular properties are attributed to 1) the rigid insertion loop at Tyr60A, and 2) a partially inaccessible RGD sequence. The former can interact with cells in the native form; the latter would appear to be presented only in an (at least partially) unfolded state. The membrane binding properties of prothrombin can be understood from the ordered arrangement of calcium ions on binding to the Gla domain. Kringle F2 binds to thrombin at the heparin binding site through charge complementarity; a conformational change appears to occur on binding. The observed rigidity of the thrombin molecule in its complexes makes thrombin ideal for structure based drug design. Thrombin can be inhibited either at the active site or at the fibrinogen recognition exosite, or both.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A player of many parts: the spotlight falls on thrombin's structure. 846 68

Reproducible disseminated intravascular coagulation in rabbits was provoked by two intravenous injections 24 hours apart of endotoxin from Salmonella enteritidis. There were mild symptoms of DIC before the second injection which considerably increased thereafter. In detail there was a sharp drop of the platelet count and a considerable diminution of Antithrombin III, of Protein C, Plasminogen and Antiplasmin as well as an appearance of fibrin monomer complexes and an increase of the aPTT. When PEG-hirudin in a single dose of 1 mg/kg BW was given simultaneously with the second injection of endotoxin the following alterations were observed: The drop of the platelet count and of the activities of Antithrombin III, Protein C, Plasminogen and Antiplasmin was significantly less pronounced. The fibrin monomer complexes were lower and the aPTT was less prolonged. The thrombin time, however, as a sign of a direct action of hirudin on thrombin was considerably more prolonged than in the controls. The combined effect of these alterations strongly points in the direction of a favourable influence of PEG-hirudin on the course of DIC. It is of special interest that 6 h after the intravenous injection of PEG-hirudin its full effect on the thrombin time was still detectable. This is apparently due to a longer half-life in circulation of PEG-hirudin than of natural hirudin.
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PMID:The effect of a long-acting recombinant hirudin (PEG-hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits. 847 80

BACKGROUND AND DESIGN--Protein C is a vitamin K-dependent plasma protein that is converted to the serine protease activated protein C by the thrombin-thrombomodulin complex. Activated protein C functions as a natural anticoagulant by inactivating the cofactors of the coagulation cascade, factors Va and VIIIa. Coumarin (warfarin)-induced skin necrosis is thought to be due to a rapid elimination of protein C relative to other vitamin K-dependent factors during the initial phase of oral anticoagulation. We have used a highly purified protein C concentrate to treat a patient with acquired protein C deficiency who developed skin necrosis during the initial phase of oral anticoagulant therapy. OBSERVATIONS AND CONCLUSIONS--During protein C concentrate therapy, no further skin lesions appeared, and the healing process of necrotic areas was facilitated. Replacement therapy with protein C concentrate appears to be safe and effective as an adjunctive treatment for coumarin-induced skin necrosis.
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PMID:Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate. 850 82


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