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  1. Article ; Online: A common protein C inhibitor exosite partially controls the heparin induced activation and inhibition of serine proteases.

    Siddiqui, Urfi / Khan, Abdul Burhan / Ahmad, Tahif / Rehman, Ahmed Abdur / Jairajpuri, Mohamad Aman

    International journal of biological macromolecules

    2024  Volume 266, Issue Pt 2, Page(s) 131065

    Abstract: Protein C inhibitor (PCI) maintains hemostasis by inhibiting both procoagulant and anticoagulant serine proteases, and plays important roles in coagulation, fibrinolysis, reproduction, and anti-angiogenesis. The reactive site loop of PCI traps and ... ...

    Abstract Protein C inhibitor (PCI) maintains hemostasis by inhibiting both procoagulant and anticoagulant serine proteases, and plays important roles in coagulation, fibrinolysis, reproduction, and anti-angiogenesis. The reactive site loop of PCI traps and irreversibly inhibits the proteases like APC (activating protein C), thrombin (FIIa) and factor Xa (FXa). Previous studies on antithrombin (ATIII) had identified Tyr253 and Glu255 as functional exosites that interact and aid in the inhibition of factor IXa and FXa. Presence of exosite in PCI is not known, however a sequence comparison with the PCI from different vertebrate species and ATIII identified Glu239 to be absolutely conserved. PCI residues analogous to ATIII exosite residues were mutated to R238A and E239A. Purified variant PCI in the presence of heparin (10 μg/ml) showed a 2-4 fold decrease in the rate of inhibition of the proteases. However, the stoichiometry of inhibition of FIIa, APC, and FXa by native PCI, R238A and E239A variants were found to be close to 1.0, which also indicated the formation of stable complexes based on SDS-PAGE and western blot analysis with thrombin and APC. Our findings revealed the possible presence of an exosite in PCI that influences the protease inhibition rates.
    MeSH term(s) Protein C Inhibitor/chemistry ; Protein C Inhibitor/metabolism ; Heparin/chemistry ; Heparin/pharmacology ; Humans ; Serine Proteases/metabolism ; Serine Proteases/chemistry ; Thrombin/metabolism ; Protein C/metabolism ; Protein C/chemistry ; Factor Xa/metabolism ; Factor Xa/chemistry ; Amino Acid Sequence ; Enzyme Activation/drug effects
    Chemical Substances Protein C Inhibitor ; Heparin (9005-49-6) ; Serine Proteases (EC 3.4.-) ; Thrombin (EC 3.4.21.5) ; Protein C ; Factor Xa (EC 3.4.21.6)
    Language English
    Publishing date 2024-03-21
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2024.131065
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Protein disulfide isomerase uses thrombin-antithrombin complex as a template to bind its target protein and alter the blood coagulation rates.

    Khan, Abdul Burhan / Siddiqui, Urfi / Fatima, Sana / Rehman, Ahmed Abdur / Jairajpuri, Mohamad Aman

    Bioscience reports

    2024  

    Abstract: During inflammation and situations of cellular stress Protein Disulfide Isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to influence thrombosis. The addition of exogenous PDI makes the environment pro-thrombotic by ...

    Abstract During inflammation and situations of cellular stress Protein Disulfide Isomerase (PDI) is released in the blood plasma from the platelet and endothelial cells to influence thrombosis. The addition of exogenous PDI makes the environment pro-thrombotic by inducing disulfide bond formation in specific plasma protein targets like vitronectin, factor V, and factor XI. However, the mechanistic details of PDI interaction with its target remain largely unknown. A decrease in the coagulation time was detected in activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in addition to the purified recombinant PDI (175nM). The coagulation time can be controlled using an activator (quercetin penta sulfate, QPS) or an inhibitor (Quercetin 3-rutinoside, Q3R) of PDI activity. Likewise, the PDI variants that increase the PDI activity (H399R) decrease, and the variant with low activity (C53A) increases the blood coagulation time. An SDS-PAGE and western blot analysis showed that the PDI does not form a stable complex with either thrombin or Antithrombin (ATIII) but it uses the ATIII-thrombin complex as a template to bind and maintain its activity. A complete inhibition of thrombin activity on the formation of ATIII-thrombin-PDI complex, and the complex-bound PDI-catalyzed disulfide bond formation of the target proteins may control the pro- and anti-thrombotic role of PDI.
    Language English
    Publishing date 2024-04-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 764946-0
    ISSN 1573-4935 ; 0144-8463
    ISSN (online) 1573-4935
    ISSN 0144-8463
    DOI 10.1042/BSR20231540
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Naringin binds to protein disulfide isomerase to inhibit its activity and modulate the blood coagulation rates: Implications in controlling thrombosis

    Khan, Abdul Burhan / Siddiqui, Urfi / Fatima, Sana / Rehman, Ahmed Abdur / Jairajpuri, Mohamad Aman

    International Journal of Biological Macromolecules. 2023, p.126241-

    2023  , Page(s) 126241–

    Abstract: Currently used antithrombotic drugs are beset with several drawbacks which necessitates the need for new and cheaper alternatives. Protein disulfide isomerase (PDI) is secreted in the blood plasma in cellular stress conditions and initiates the thrombus ... ...

    Abstract Currently used antithrombotic drugs are beset with several drawbacks which necessitates the need for new and cheaper alternatives. Protein disulfide isomerase (PDI) is secreted in the blood plasma in cellular stress conditions and initiates the thrombus formation. A screening of library of natural compounds revealed that naringin had a high binding affinity for the PDI (−8.2 kcal/mol). Recombinant PDI was purified using the affinity chromatography. Incubation of purified PDI (3 μM) with naringin (0-100 μM, pH 7.4, 25 °C) partially modulated its conformation. Consequently, the fluorescence emission spectra of the PDI binding to naringin were assessed using the Stern-Volmer equation, which indicated an association constant of 2.78 × 10⁴ M⁻¹ suggesting an appreciable affinity for the naringin, with a unique binding site. An insulin turbidity assay showed that PDI activity is decreased in the presence of naringin indicating inhibition. Molecular dynamic simulation studies showed the changes in the PDI structure on binding to the naringin. Incubation of naringin (80 μM) in fresh human plasma along with exogenous PDI (175 nM) showed a significant delay in the intrinsic and extrinsic coagulation pathways. We show that naringin is able to modulate the PDI conformation and activity resulting in altered blood coagulation rates.
    Keywords affinity chromatography ; blood coagulation ; blood plasma ; coagulation ; equations ; fluorescence ; humans ; insulin ; naringin ; pH ; protein disulfide-isomerase ; thrombosis ; turbidity ; Protein disulfide isomerase ; Anticoagulant
    Language English
    Publishing place Elsevier B.V.
    Document type Article ; Online
    Note Pre-press version
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2023.126241
    Database NAL-Catalogue (AGRICOLA)

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    Zs.B 2374: Show issues Location:
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  4. Article ; Online: Naringin binds to protein disulfide isomerase to inhibit its activity and modulate the blood coagulation rates: Implications in controlling thrombosis.

    Khan, Abdul Burhan / Siddiqui, Urfi / Fatima, Sana / Rehman, Ahmed Abdur / Jairajpuri, Mohamad Aman

    International journal of biological macromolecules

    2023  Volume 252, Page(s) 126241

    Abstract: Currently used antithrombotic drugs are beset with several drawbacks which necessitates the need for new and cheaper alternatives. Protein disulfide isomerase (PDI) is secreted in the blood plasma in cellular stress conditions and initiates the thrombus ... ...

    Abstract Currently used antithrombotic drugs are beset with several drawbacks which necessitates the need for new and cheaper alternatives. Protein disulfide isomerase (PDI) is secreted in the blood plasma in cellular stress conditions and initiates the thrombus formation. A screening of library of natural compounds revealed that naringin had a high binding affinity for the PDI (-8.2 kcal/mol). Recombinant PDI was purified using the affinity chromatography. Incubation of purified PDI (3 μM) with naringin (0-100 μM, pH 7.4, 25 °C) partially modulated its conformation. Consequently, the fluorescence emission spectra of the PDI binding to naringin were assessed using the Stern-Volmer equation, which indicated an association constant of 2.78 × 10
    MeSH term(s) Humans ; Protein Disulfide-Isomerases/metabolism ; Blood Coagulation ; Thrombosis/metabolism ; Flavanones/pharmacology
    Chemical Substances Protein Disulfide-Isomerases (EC 5.3.4.1) ; naringin (N7TD9J649B) ; Flavanones
    Language English
    Publishing date 2023-08-09
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2023.126241
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 2374: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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