Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase
Aims: Design and synthesis of a novel 3, 3′, 4′, 5, 7-O- pentasulfated Quercetin (QPS) as an activator of protein disulfide isomerase (PDI). Main Methods: Based on an in silico analysis we show that QPS binds to a and b domain of PDI (−7.4 kcal/mol) unlike PDI inhibitor quercetin 3-rutinoside (Q3R)...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | Medicine in Drug Discovery |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590098620300166 |
| _version_ | 1818283396376297472 |
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| author | Abdul Burhan Khan Neha Gupta Qudsia Rashid Irshad Ahmad Shadabi Bano Urfi Siddiqui Mohammad Abid Mohamad Aman Jairajpuri |
| author_facet | Abdul Burhan Khan Neha Gupta Qudsia Rashid Irshad Ahmad Shadabi Bano Urfi Siddiqui Mohammad Abid Mohamad Aman Jairajpuri |
| author_sort | Abdul Burhan Khan |
| collection | DOAJ |
| description | Aims: Design and synthesis of a novel 3, 3′, 4′, 5, 7-O- pentasulfated Quercetin (QPS) as an activator of protein disulfide isomerase (PDI). Main Methods: Based on an in silico analysis we show that QPS binds to a and b domain of PDI (−7.4 kcal/mol) unlike PDI inhibitor quercetin 3-rutinoside (Q3R) that binds at substrate-binding domain b (−8.0 kcal/mol). QPS was synthesized and its structure validated using a combination of FTIR, NMR and mass spectral studies. Surprisingly, unlike Q3R QPS is shown to enhance the activity of purified recombinant PDI. Fluorometric and circular dichroism analysis showed that QPS binds to a unique site on PDI with marginal variations in its secondary structure. Key Findings: Hypersulfation of quercetin reverses its inhibitory effect on PDI as addition of exogenous PDI and QPS in human plasma showed increase in rate of coagulation, unlike Q3R which shows a decrease. Significance: The results indicate QPS to be a novel enhancer of PDI activity that can influence the coagulation rates in plasma. QPS has therapeutic potential to control bleeding. |
| first_indexed | 2024-12-13T00:36:15Z |
| format | Article |
| id | doaj.art-e47d85849f204629b12cf9b0327165f8 |
| institution | Directory Open Access Journal |
| issn | 2590-0986 |
| language | English |
| last_indexed | 2024-12-13T00:36:15Z |
| publishDate | 2020-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Medicine in Drug Discovery |
| spelling | doaj.art-e47d85849f204629b12cf9b0327165f82022-12-22T00:05:13ZengElsevierMedicine in Drug Discovery2590-09862020-06-016100029Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomeraseAbdul Burhan Khan0Neha Gupta1Qudsia Rashid2Irshad Ahmad3Shadabi Bano4Urfi Siddiqui5Mohammad Abid6Mohamad Aman Jairajpuri7Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, IndiaProtein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, IndiaProtein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, IndiaProtein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, IndiaProtein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, IndiaProtein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, IndiaOrganic Synthesis Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, IndiaProtein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, India; Corresponding author at: Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia University, Jamia Nagar, New-Delhi 110025, India.Aims: Design and synthesis of a novel 3, 3′, 4′, 5, 7-O- pentasulfated Quercetin (QPS) as an activator of protein disulfide isomerase (PDI). Main Methods: Based on an in silico analysis we show that QPS binds to a and b domain of PDI (−7.4 kcal/mol) unlike PDI inhibitor quercetin 3-rutinoside (Q3R) that binds at substrate-binding domain b (−8.0 kcal/mol). QPS was synthesized and its structure validated using a combination of FTIR, NMR and mass spectral studies. Surprisingly, unlike Q3R QPS is shown to enhance the activity of purified recombinant PDI. Fluorometric and circular dichroism analysis showed that QPS binds to a unique site on PDI with marginal variations in its secondary structure. Key Findings: Hypersulfation of quercetin reverses its inhibitory effect on PDI as addition of exogenous PDI and QPS in human plasma showed increase in rate of coagulation, unlike Q3R which shows a decrease. Significance: The results indicate QPS to be a novel enhancer of PDI activity that can influence the coagulation rates in plasma. QPS has therapeutic potential to control bleeding.http://www.sciencedirect.com/science/article/pii/S2590098620300166Protein Disulfide IsomeraseThrombosisQuercetinCoagulationNovel anticoagulant |
| spellingShingle | Abdul Burhan Khan Neha Gupta Qudsia Rashid Irshad Ahmad Shadabi Bano Urfi Siddiqui Mohammad Abid Mohamad Aman Jairajpuri Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase Medicine in Drug Discovery Protein Disulfide Isomerase Thrombosis Quercetin Coagulation Novel anticoagulant |
| title | Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase |
| title_full | Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase |
| title_fullStr | Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase |
| title_full_unstemmed | Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase |
| title_short | Quercetin 3, 3′, 4′, 5, 7-O- pentasulfate (QPS): A novel activator of protein disulfide isomerase |
| title_sort | quercetin 3 3 4 5 7 o pentasulfate qps a novel activator of protein disulfide isomerase |
| topic | Protein Disulfide Isomerase Thrombosis Quercetin Coagulation Novel anticoagulant |
| url | http://www.sciencedirect.com/science/article/pii/S2590098620300166 |
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