Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Survival of the implanting human blastocyst requires that trophoblasts gain access to the maternal circulation. This is initially achieved when syncytiotrophoblasts breach endometrial capillarlies and venules. Subsequently, extravillous cytotrophoblasts penetrate the spiral arteries to induce their morphological transformation into high-flow, low-resistance vessels. This process provides the embryo with a requisite source of oxygen and nutrients, but risks decidual hemorrhage leading to abortion and abruption. Endovascular trophoblast invasion occurs within a matrix of decidualizing endometrial stromal cells. These decidual cells are temporally and spatially positioned to create a local hemostatic milieu which can counteract the threat of hemorrhage. Prior studies from our laboratory have established that decidual cells of luteal phase and pregnant endometrium express two crucial modulators of hemostasis: 1) tissue factor (TF), the primary initiator of hemostasis via factor Xa activation; and 2) plasminogen activator inhibitor type 1 (PAI-1), the fast inhibitor of the primary fibrinolytic agent, tissue type plasminogen activator. This coordinate increase in TF and PAI-1 expression provides a mechanism by which decidual cells control local hemostasis during endovascular trophoblast invasion. Cultures of human endometrial stromal cells and decidual cells isolated from first trimester endometrium demonstrate that progestins enhance TF and PAI-1 protein and mRNA expression via the induction of crucial intermediate transcription factors. Integration of these in vivo observations and in vitro studies suggest a model by which decidua acts to maintain hemostasis during implantation and placentation.
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PMID:The decidua regulates hemostasis in human endometrium. 1040 75

Under normal conditions activated protein C is a natural anticoagulant that cleaves 2 activated coagulation factors, factor Va and factor VIIIa, thereby inhibiting the conversion of factor X to factor Xa and of prothrombin to thrombin. Additionally, activated protein C enhances tissue-plasminogen activator-mediated fibrinolysis by inhibition of plasminogen activator inhibitor-1. This results in an increase in circulatory plasminogen activator levels. Protein C deficiency, a genetic or acquired thrombophilic abnormality, has been demonstrated to predispose to episodes of potentially blinding and lethal thromboembolic events. Heterozygous-deficient subjects usually remain asymptomatic until adolescence or adulthood. In homozygous-deficient patients, protein C activity is usually less than 1% (reference range, 70%-140%), resulting in thromboembolism as early as in the neonatal period. The major clinical symptoms in affected newborn infants have been purpura fulminans, vitreous hemorrhage, and central nervous system thrombosis. The age of onset of the first symptoms has ranged from a few hours to 2 weeks after birth, usually after an uncomplicated full-term pregnancy and delivery. In contrast to the genetic form, acquired neonatal protein C deficiency occurs particularly in ill preterm babies. Typical complications of prematurity such as respiratory distress syndrome, necrotizing enterocolitis, and neonatal sepsis may also be present. In the medical literature, there are only a few reports of homozygous protein C deficiency in neonates. We present 2 cases of homozygous protein C deficiency with ocular and extraocular manifestation.
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PMID:Ophthalmic manifestation of congenital protein C deficiency. 1042 94

The serine proteinase plasmin is, together with tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), involved in the dissolution of blood clots in a fibrin-dependent manner. Moreover, plasmin plays a key role in a variety of other activation cascades such as the activation of metalloproteinases, and has also been implicated in wound healing, pathogen invasion, cancer invasion and metastasis. The leech-derived (Hirudo medicinalis) antistasin-type inhibitor bdellastasin represents a specific inhibitor of trypsin and plasmin and thus offers a unique opportunity to evaluate the concept of plasmin inhibition. The complexes formed between bdellastasin and bovine as well as porcine beta-trypsin have been crystallised in a monoclinic and a tetragonal crystal form, containing six molecules and one molecule per asymmetric unit, respectively. Both structures have been solved and refined to 3.3 A and 2.8 A resolution. Bdellastasin turns out to have an antistasin-like fold exhibiting a bis-domainal structure like the tissue kallikrein inhibitor hirustasin. The interaction between bdellastasin and trypsin is restricted to the C-terminal subdomain of bdellastasin, particularly to its primary binding loop, comprising residues Asp30-Glu38. The reactive site of bdellastasin differs from other antistasin-type inhibitors of trypsin-like proteinases, exhibiting a lysine residue instead of an arginine residue at P1. A model of the bdellastasin-microplasmin complex has been created based on the X-ray structures. Our modelling studies indicate that both trypsin and microplasmin recognise bdellastasin by interactions which are characteristic for canonically binding proteinase inhibitors. On the basis of our three-dimensional structures, and in comparison with the tissue-kallikrein-bound and free hirustasin and the antistasin structures, we postulate that the binding of the inhibitors toward trypsin and plasmin is accompanied by a switch of the primary binding loop segment P5-P3. Moreover, in the factor Xa inhibitor antistasin, the core of the molecule would prevent an equivalent rotation of the P3 residue, making exosite interactions of antistasin with factor Xa imperative. Furthermore, Arg32 of antistasin would clash with Arg175 of plasmin, thus impairing a favourable antistasin-plasmin interaction and explaining its specificity.
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PMID:Structure of the complex of the antistasin-type inhibitor bdellastasin with trypsin and modelling of the bdellastasin-microplasmin system. 1051 18

The GUSTO-I trial provided definitive evidence that early and complete thrombolysis are closely associated with clinical outcome. However, in this trial the best thrombolytic strategy, consisting of accelerated t-PA, aspirin, and heparin, only yielded restoration of brisk flow (TIMI 3) in 54% of patients at 90 minutes after therapy. There are a variety of new strategies aimed at improving the rate of early TIMI flow, consisting of new plasminogen activators, anticoagulants, and platelet inhibitors, The third generation plasminogen activators include reteplase (r-PA), n-PA, bat-PA, staphylokinase, and TNK. To date, none of these molecules have been clearly associated with superior rates of infarct vessel patency, but comparative trials are in progress. Potent inhibitors of thrombin are recombinant hirudin, the most potent naturally occurring anticoagulant known, and synthetic direct thrombin inhibitors such as hirulog and argatroban. In the years ahead, agents that block the generation of thrombin, a step higher up in the coagulation cascade, such as factor Xa inhibitors, will be clinically pursued. The platelet glycoprotein Ilb/Illa inhibitors are a potent class of agents directed against the final common pathway for platelet aggregation, and pilot studies suggest excellent potential for facilitating early thrombolysis. Accordingly, a multitiered strategy of improved plasminogen activators, thrombin inhibitors, and antiplatelets is likely to result in far better clinical outcomes for myocardial reperfusion therapy in the future.
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PMID:Potential for a New Coronary Thrombolytic Plateau. 1060 53

The orthopoxvirus serpin SPI-3 is N-glycosylated and suppresses fusion between infected cells. Although SPI-3 contains motifs conserved in inhibitory serpins, no proteinase inhibition by SPI-3 has been demonstrated, and mutations within the serpin reactive center loop (RCL) do not affect the ability to regulate cell fusion. We demonstrate here that SPI-3 protein expressed by transcription/translation in vitro is able to form SDS-stable complexes with the serine proteinases plasmin, urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA), consistent with inhibitory activity of the serpin. Weaker complexes were noted with factor Xa and thrombin. Mutation of Arg-340/Ser-341 at the predicted P1/P1' sites within the RCL prevented the formation of complexes between SPI-3 and plasmin, uPA, or tPA, suggesting that the arginine at the P1 position was required for complex formation. SPI-3 protein lacking the N-terminal signal peptide was purified by means of an N-terminal His(10)-tag and gave complete inhibition in vitro of plasmin, uPA, and tPA and partial inhibition of factor Xa. SPI-3 is therefore a bifunctional protein that acts as a proteinase inhibitor and suppresses infected cell-cell fusion. As a proteinase inhibitor, SPI-3 has similar specificity to the leporipoxvirus SERP1 protein of myxoma virus, although the two serpins are less than 30% identical overall. The inhibition constants of SPI-3 for plasmin, uPA, and tPA were determined to be 0.64, 0.51, and 1.9 nM, respectively, very similar to the corresponding K(i) values of SERP1.
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PMID:The cowpox virus serpin SPI-3 complexes with and inhibits urokinase-type and tissue-type plasminogen activators and plasmin. 1087 70

RPR 130737 inhibited factor Xa (FXa) with a Ki of 2.4 nM and also displayed excellent specificity toward FXa relative to other serine proteases. It showed selectivity of more than 1000-fold over thrombin, activated protein C, plasmin, tissue-plasminogen activator and trypsin. RPR 130737 prolonged plasma activated partial thromboplastin time and prothrombin time in a dose-dependent fashion. In the activated partial thromboplastin time assay, the concentrations required for doubling coagulation time were 0.32 microM (human), 0.61 microM (monkey), 0.44 microM (dog), 0.15 microM (rabbit), and 0.82 microM (rat). The concentrations required to double prothrombin time were 0.86 microM (human), and 1.26 microM (monkey), 1.15 microM (dog), 0.39 microM (rabbit) and 7.31 microM (rat). Kinetic studies revealed that RPR 130737 was a fast binding, reversible and competitive inhibitor for FXa when Spectrozyme FXa, a chromogenic substrate, was used. A coupled-enzyme assay measuring thrombin activity following prothrombinase conversion of prothrombin to thrombin indicated that RPR 130737 was a potent inhibitor for prothrombinase-bound FXa. In this assay, RPR 130737 showed IC50s of 17 nM and 35.9 nM, respectively when artificial phosphatidylserine/phosphatidylcholine (PS/PC) liposomes or gel-filtered platelets were used as the phospholipid source. An FX-deficient plasma clotting-time correction assay further demonstrated that RPR 130737 was a specific inhibitor of FXa. RPR 130737 showed no effect on platelet aggregation in vitro. These results indicate that RPR 130737 has the potential to be developed as an antithrombotic agent based on its potent and selective inhibitory effect against FXa.
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PMID:In vitro characterization of a novel factor Xa inhibitor, RPR 130737. 1101 77

Secreted phospholipases A(2) (sPLA(2)s) form a large family of structurally related enzymes which are widespread in nature. Snake venoms are known for decades to contain a tremendous molecular diversity of sPLA(2)s which can exert a myriad of toxic and pharmacological effects. Recent studies indicate that mammalian cells also express a variety of sPLA(2)s with ten distinct members identified so far, in addition to the various other intracellular PLA(2)s. Furthermore, scanning of nucleic acid databases fueled by the different genome projects indicates that several sPLA(2)s are also present in invertebrate animals like Drosophila melanogaster as well as in plants. All of these sPLA(2)s catalyze the hydrolysis of glycerophospholipids at the sn-2 position to release free fatty acids and lysophospholipids, and thus could be important for the biosynthesis of biologically active lipid mediators. However, the recent identification of a variety of membrane and soluble proteins that bind to sPLA(2)s suggests that the sPLA(2) enzymes could also function as high affinity ligands. So far, most of the binding data have been accumulated with venom sPLA(2)s and group IB and IIA mammalian sPLA(2)s. Collectively, venom sPLA(2)s have been shown to bind to membrane and soluble mammalian proteins of the C-type lectin superfamily (M-type sPLA(2) receptor and lung surfactant proteins), to pentraxin and reticulocalbin proteins, to factor Xa and to N-type receptors. Venom sPLA(2)s also associate with three distinct types of sPLA(2) inhibitors purified from snake serum that belong to the C-type lectin superfamily, to the three-finger protein superfamily and to proteins containing leucine-rich repeats. On the other hand, mammalian group IB and IIA sPLA(2)s can bind to the M-type receptor, and group IIA sPLA(2)s can associate with lung surfactant proteins, factor Xa and proteoglycans including glypican and decorin, a mammalian protein containing a leucine-rich repeat.
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PMID:Increasing molecular diversity of secreted phospholipases A(2) and their receptors and binding proteins. 1108 Jun 77

Inhibition of factor Xa (FXa) attenuates thrombus progression. This study was designed to determine whether a novel, synthetic inhibitor of FXa (ZK-807834, molecular mass 527 Da, K(i) = 0.11 nM) administered during and briefly after pharmacologic coronary fibrinolysis increases 24-h patency. Either ZK-807834 (< or = 1.6 mg/kg, n = 10; 6.5 mg/kg, n = 8; or 13 mg/kg, n = 7); a peptide inhibitor of FXa, recombinant tick anticoagulant peptide (rTAP, 13.6 mg/kg, n = 7); heparin (150 U/kg bolus and 50 U/kg/h infusion) and aspirin (5 mg/kg) (n = 7); or saline as a control (n = 13) were administered i.v. over 135 min in conscious dogs after thrombotic occlusion induced by electrical injury to a coronary artery. Fibrinolysis was induced with recombinant human tissue-type plasminogen activator (1.0 mg/kg i.v. over 1 h), and patency was monitored continuously for 24 h with an implanted Doppler probe. Reocclusion occurred in all control and heparin/aspirin-treated dogs within 1 h after fibrinolysis. High dose ZK-807834 prevented reocclusion in five of six dogs and delayed reocclusion in the other dog (186 min after recanalization, p = 0.0005 versus heparin/aspirin). Reocclusion was delayed (406 +/- 329 min), but still occurred in three of six rTAP-treated dogs (p = 0.003 versus heparin/aspirin). Patency after 24 h was 100% in ZK-807834-treated and rTAP-treated dogs compared with 67% in control and 83% in heparin/aspirin-treated dogs. PT was increased 3.7-fold, activated partial thromboplastin time 4.9-fold, and bleeding time 2.5-fold by high dose ZK-807834 compared with 1.2-fold, 11.5-fold, and 2.3-fold, respectively, for heparin/aspirin. Inhibition of FXa with ZK-807834 decreases reocclusion and improves patency of recanalized arteries without increasing bleeding compared with heparin/aspirin.
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PMID:A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs. 1116 Jun 45

Sepimostat mesilate (FUT-187: 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethane sulfonate) is a newly synthesized serine protease inhibitor. In the present study, the oral administration of FUT-187 inhibited stasis-induced venous thrombosis in rats. We supposed that such effect of this compound was caused by its inhibitory effect on coagulation. However, the dose of FUT-187 that was effective at inhibiting thrombosis (10 and 30 mg/kg, po) had no effect on the plasma recalcification time (PRCT), activated partial thromboplastin time (APTT) and prothrombin time (PT) in rats. Therefore, we investigated the fibrinolytic activity of FUT-187 in rat plasma. The results revealed that rat plasma after FUT-187 administration exhibited increased amidolytic activity for a plasmin-, tissue-type plasminogen activator (t-PA)-, urokinase-type plasminogen activator (u-PA)-, factor Xa-, factor XIa- and factor XIIa-sensitive synthetic peptide substrate. On the other hand, the inhibitory effect of FUT-187 in the thrombosis model was not affected by additional treatment with epsilon-amino-n-caproic acid (EACA), a plasmin-mediated fibrinolysis inhibitor. These results suggest that even if FUT-187 enhanced fibrinolysis, it would be independent of a plasmin-mediated fibrinolytic pathway. To characterize the fibrinolytic activity, which might reduce the thrombus weight in the thrombosis model administered FUT-187, we carried out fibrinogen zymography, and clarified that FUT-187 enhanced the formation of a 20-kDa fibrinolytic fragment. Interestingly, this fragment was not affected by t-PA. Consequently, we consider that the inhibitory effect of FUT-187 on venous thrombosis model is caused by fibrinolysis, which is attributable to the 20-kDa fragment, rather than by inhibition of thrombus formation.
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PMID:Effect of sepimostat mesilate on experimental venous thrombosis in rats. 1122 42

FXV673 is a novel, potent, and selective factor Xa (FXa) inhibitor. FXV673 inhibited human, dog, and rabbit FXa with a K(i) of 0.52, 1.41, and 0.27 nM, respectively. FXV673 also displayed excellent specificity toward FXa relative to other serine proteases. It showed selectivity of more than 1000-fold over thrombin, activated protein C (aPC), plasmin, and tissue-plasminogen activator (t-PA). FXV673 prolonged plasma activated partial thromboplastin time (APTT) and prothrombin time (PT) in a dose-dependent fashion. In the APTT assays, the concentrations (microM) required for doubling coagulation time were 0.41 (human), 0.65 (monkey), 1.12 (dog), 0.25 (rabbit), and 0.80 (rat). The concentrations (microM) required in the PT assays were 1.1 (human), 1.32 (monkey), 2.31 (dog), 0.92 (rabbit), and 1.69 (rat). A coupled-enzyme assay was performed to measure thrombin activity following prothrombinase conversion of prothrombin to thrombin. FXV673 showed IC(50)s of 1.38 and 2.55 nM, respectively, when artificial phosphatidylserine/phosphatidylcholine (PS/PC) liposomes or fresh platelets were used as the phospholipid source for prothrombinase complex formation. It was demonstrated that FXV673 could inhibit further thrombin generation in the prothrombinase complex using PS/PC liposomes. FXV673 dose-dependently prolonged the time to vessel occlusion and inhibited thrombus formation in well-characterized canine models of thrombosis. Interspecies extrapolation (approximately 2.5-fold higher sensitivity for FXa inhibition in human than in dog) suggested that 100 ng/ml of FXV673 would be an effective plasma concentration for clinical studies. Currently FXV673 is undergoing clinical studies to be developed as an antithrombotic agent.
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PMID:Pharmacological characterization of a novel factor Xa inhibitor, FXV673. 1156 41


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