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Thapsigargin is a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). Structurally, thapsigargin is classified as a guaianolide, and is extracted from a plant, Thapsia garganica. It is a tumor promoter in mammalian cells.

Thapsigargin
Names
Preferred IUPAC name
(3S,3aR,4S,6S,6aR,7S,8S,9bS)-3,3a-Dihydroxy-3,6,9-trimethyl-2-oxo-2,3,3a,4,5,6,6a,7,8,9b-decahydroazuleno[4,5-b]furan-4,6,7,8-tetrayl 6-acetate 4-butanoate 8-[(2Z)-2-methylbut-2-enoate] 7-octanoate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.116.539
UNII
  • InChI=1S/C34H50O12/c1-9-12-13-14-15-17-24(37)43-28-26-25(20(5)27(28)44-30(38)19(4)11-3)29-34(41,33(8,40)31(39)45-29)22(42-23(36)16-10-2)18-32(26,7)46-21(6)35/h11,22,26-29,40-41H,9-10,12-18H2,1-8H3/b19-11-/t22-,26+,27-,28-,29-,32-,33+,34+/m0/s1 Y
    Key: IXFPJGBNCFXKPI-FSIHEZPISA-N Y
  • InChI=1/C34H50O12/c1-9-12-13-14-15-17-24(37)43-28-26-25(20(5)27(28)44-30(38)19(4)11-3)29-34(41,33(8,40)31(39)45-29)22(42-23(36)16-10-2)18-32(26,7)46-21(6)35/h11,22,26-29,40-41H,9-10,12-18H2,1-8H3/b19-11-/t22-,26+,27-,28-,29-,32-,33+,34+/m0/s1
    Key: IXFPJGBNCFXKPI-FSIHEZPIBR
Properties
C34H50O12
Molar mass 650.762 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Nverify (what is YN ?)

Thapsigargin raises cytosolic (intracellular) calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. Store-depletion can secondarily activate plasma membrane calcium channels, allowing an influx of calcium into the cytosol. Depletion of ER calcium stores leads to ER stress and activation of the unfolded protein response. Non-resolved ER stress can cumulatively lead to cell death. Prolonged store depletion can protect against ferroptosis via remodeling of ER-synthesized phospholipids.

Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR.

Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations and ER calcium depletion.

A study from the University of Nottingham showed promising results for its use against Covid-19 and other coronavirus.

Contents

The complete biosynthesis of thapsigargin has yet to be elucidated. A proposed biosynthesis starts with the farnesyl pyrophosphate. The first step is controlled by the enzyme germacrene B synthase. In the second step, the C(8) position is easily activated for an allylic oxidation due to the position of the double bond. The next step is the addition of the acyloxy moiety by a P450 acetyltransferase; which is a well known reaction for the synthesis of the diterpene, taxol. In the third step, the lactone ring is formed by a cytochrome P450 enzyme using NADP+. With the butyloxy group on the C(8), the formation will only generate the 6,12-lactone ring. The fourth step is an epoxidation that initiates the last step of the base guaianolide formation. In the fifth step, a P450 enzyme closes the 5 + 7 guaianolide structure. The ring closing is important, because it will proceed via 1,10 - epoxidation in order to retain the 4,5 - double bond needed in thapsigargin. It is not known whether the secondary modifications to the guaianolide occur before, or after the formation of thapsigargin, but will need to be considered when elucidating the true biosynthesis. It should also be noted, that several of these enzymes are P450s, therefore oxygen and NADPH are likely crucial to this biosynthesis as well as other cofactors such as Mg2+ and Mn2+ may be needed.

Since inhibition of SERCA is a mechanism of action that has been used to target solid tumors, thapsigargin has attracted research interest. A prodrug of thapsigargin, mipsagargin, is currently undergoing clinical trials for the treatment of glioblastoma.

The biological activity has also attracted research into the laboratory synthesis of thapsigargin. To date, three distinct syntheses have been reported: one by Steven V. Ley, one by Phil Baran., and one by P. Andrew Evans.

Preclinical studies demonstrated that other effects of thapsigargin include suppression of nicotinic acetylcholine receptors activity in neurons of the guinea-pig ileum submucous plexus and rat superior cervical ganglion.

Laboratory studies at the University of Nottingham, using in vitro cell cultures, indicates possible potential as a broad spectrum antiviral, with activity against the COVID-19 virus (SARS-CoV-2), a common cold virus, respiratory syncytial virus (RSV), and the influenza A virus.

  1. Rogers TB, Inesi G, Wade R, Lederer WJ (1995). "Use of thapsigargin to study Ca2+ homeostasis in cardiac cells". Biosci. Rep. 15 (5): 341–9. doi:10.1007/BF01788366. PMID 8825036. S2CID 29613387.
  2. Rasmussen U, Brøogger Christensen S, Sandberg F (1978). "Thapsigargine and thapsigargicine, two new histamine liberators from Thapsia garganica L.". Acta Pharm. Suec. 15 (2): 133–140. PMID 79299.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. Hakii, H.; Fujiki, H.; Suganuma, M.; Nakayasu, M.; Tahira, T.; Sugimura, T.; Scheuer, P. J.; Christensen, S. B. (1986). "Thapsigargin, a histamine secretagogue, is a non-12-O-tetradecanolphorbol-13-acetate (TPA) type tumor promoter in two-stage mouse skin carcinogenesis". Journal of Cancer Research and Clinical Oncology. 111 (3): 177–181. doi:10.1007/BF00389230. PMID 2426275. S2CID 19093742.
  4. Malhotra, Jyoti D.; Kaufman, Randal J. (December 2007). "The endoplasmic reticulum and the unfolded protein response". Seminars in Cell & Developmental Biology. 18 (6): 716–731. doi:10.1016/j.semcdb.2007.09.003. PMC2706143. PMID 18023214.
  5. Hetz, Claudio; Papa, Feroz R. (January 2018). "The Unfolded Protein Response and Cell Fate Control". Molecular Cell. 69 (2): 169–181. doi:10.1016/j.molcel.2017.06.017. PMID 29107536.
  6. Sano, Renata; Reed, John C. (2013-12-01). "ER stress-induced cell death mechanisms". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1833 (12): 3460–3470. doi:10.1016/j.bbamcr.2013.06.028. ISSN 0167-4889. PMC3834229. PMID 23850759.
  7. Xin, Shan; Mueller, Constanze; Pfeiffer, Susanne; Kraft, Vanessa A. N.; Merl-Pham, Juliane; Bao, Xuanwen; Feederle, Regina; Jin, Xiang; Hauck, Stefanie M.; Schmitt-Kopplin, Philippe; Schick, Joel A. (2021-10-18). "MS4A15 drives ferroptosis resistance through calcium-restricted lipid remodeling". Cell Death & Differentiation. 29 (3): 670–686. doi:10.1038/s41418-021-00883-z. ISSN 1476-5403. PMC8901757. PMID 34663908. S2CID 239025829.
  8. Engedal, Nikolai; Torgersen, Maria L; Guldvik, Ingrid J; Barfeld, Stefan J; Bakula, Daniela; Sætre, Frank; Hagen, Linda K; Patterson, John B; Proikas-Cezanne, Tassula (2013-10-25). "Modulation of intracellular calcium homeostasis blocks autophagosome formation". Autophagy. 9 (10): 1475–1490. doi:10.4161/auto.25900. ISSN 1554-8627. PMID 23970164.
  9. Ganley, Ian G.; Wong, Pui-Mun; Gammoh, Noor; Jiang, Xuejun (2011). "Distinct Autophagosomal-Lysosomal Fusion Mechanism Revealed by Thapsigargin-Induced Autophagy Arrest"(PDF). Molecular Cell. 42 (6): 731–743. doi:10.1016/j.molcel.2011.04.024. PMC3124681. PMID 21700220.
  10. Drew, D.P.; Krichau, N.; Reichwald, K.; Simonsen, H.T. (2009). "Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis". Phytochem Rev. 8 (3): 581–599. doi:10.1007/s11101-009-9130-z. S2CID 37287410.
  11. Denmeade, S. R.; Mhaka, A. M.; Rosen, D. M.; Brennen, W. N.; Dalrymple, S; Dach, I; Olesen, C; Gurel, B; Demarzo, A. M.; Wilding, G; Carducci, M. A.; Dionne, C. A.; Møller, J. V.; Nissen, P; Christensen, S. B.; Isaacs, J. T. (2012). "Engineering a Prostate-Specific Membrane Antigen–Activated Tumor Endothelial Cell Prodrug for Cancer Therapy". Science Translational Medicine. 4 (140): 140ra86. doi:10.1126/scitranslmed.3003886. PMC3715055. PMID 22745436.
  12. Andersen, Trine; López, Carmen; Manczak, Tom; Martinez, Karen; Simonsen, Henrik (2015). "Thapsigargin—From Thapsia L. To Mipsagargin". Molecules. 20 (4): 6113–27. doi:10.3390/molecules20046113. PMC6272310. PMID 25856061.
  13. "Mipsagargin". NCI Drug Dictionary. National Cancer Institute. 2011-02-02.
  14. "Clinical Trials: Mipsagargin". National Cancer Institute. 17 August 2017.
  15. Ball, Matthew; Andrews, Stephen P.; Wierschem, Frank; Cleator, Ed; Smith, Martin D.; Ley, Steven V. (2007). "Total Synthesis of Thapsigargin, a Potent SERCA Pump Inhibitor". Organic Letters. 9 (4): 663–6. doi:10.1021/ol062947x. PMID 17256950.
  16. Chu, Hang; Smith, Joel M.; Felding, Jakob; Baran, Phil S. (2017). "Scalable Synthesis of (−)-Thapsigargin". ACS Central Science. 3 (1): 47–51. doi:10.1021/acscentsci.6b00313. PMC5269647. PMID 28149952.
  17. Chen, Dezhi; Evans, P Andrew. (2017). "A Concise, Efficient and Scalable Total Synthesis of Thapsigargin and Nortrilobolide from (R)-(-)-Carvone". J. Am. Chem. Soc. 139 (17): 6046–6049. doi:10.1021/jacs.7b01734. PMID 28422492.
  18. Glushakov, A. V.; Glushakova, H. Y.; Skok, V. I. (1999-01-15). "Modulation of nicotinic acetylcholine receptor activity in submucous neurons by intracellular messengers". Journal of the Autonomic Nervous System. 75 (1): 16–22. doi:10.1016/S0165-1838(98)00165-9. ISSN 0165-1838. PMID 9935265 – via https://doi.org/10.1016/S0165-1838(98)00165-9.{{cite journal}}:External link in |via= ()
  19. Voitenko, S. V.; Bobryshev, A. Yu; Skok, V. I. (2000-01-01). "Intracellular regulation of neuronal nicotinic cholinorceptors". Neuroscience and Behavioral Physiology. 30 (1): 19–25. doi:10.1007/BF02461388. ISSN 0097-0549. PMID 10768368. S2CID 10990124.
  20. "Powerful Antiviral Treatment for COVID-19 Discovered That Could Change How Epidemics Are Managed". 2 February 2021.

<15.Dey. S.; Bajaj, S. O "Promising anticancer drug thapsigargin: A perspective toward the total synthesis" Synthetic communication 2018, 48(1), 1-13/>

Thapsigargin Article Talk Language Watch Edit Thapsigargin is a non competitive inhibitor of the sarco endoplasmic reticulum Ca2 ATPase SERCA 1 Structurally thapsigargin is classified as a guaianolide and is extracted from a plant Thapsia garganica 2 It is a tumor promoter in mammalian cells 3 Thapsigargin NamesPreferred IUPAC name 3S 3aR 4S 6S 6aR 7S 8S 9bS 3 3a Dihydroxy 3 6 9 trimethyl 2 oxo 2 3 3a 4 5 6 6a 7 8 9b decahydroazuleno 4 5 b furan 4 6 7 8 tetrayl 6 acetate 4 butanoate 8 2Z 2 methylbut 2 enoate 7 octanoateIdentifiersCAS Number 67526 95 8 Y3D model JSmol Interactive imageChEBI CHEBI 9516 YChEMBL ChEMBL96926 NChemSpider 393753 YECHA InfoCard 100 116 539IUPHAR BPS 5351PubChem CID 446378UNII Z96BQ26RZD YCompTox Dashboard EPA DTXSID5040621InChI InChI 1S C34H50O12 c1 9 12 13 14 15 17 24 37 43 28 26 25 20 5 27 28 44 30 38 19 4 11 3 29 34 41 33 8 40 31 39 45 29 22 42 23 36 16 10 2 18 32 26 7 46 21 6 35 h11 22 26 29 40 41H 9 10 12 18H2 1 8H3 b19 11 t22 26 27 28 29 32 33 34 m0 s1 YKey IXFPJGBNCFXKPI FSIHEZPISA N YInChI 1 C34H50O12 c1 9 12 13 14 15 17 24 37 43 28 26 25 20 5 27 28 44 30 38 19 4 11 3 29 34 41 33 8 40 31 39 45 29 22 42 23 36 16 10 2 18 32 26 7 46 21 6 35 h11 22 26 29 40 41H 9 10 12 18H2 1 8H3 b19 11 t22 26 27 28 29 32 33 34 m0 s1Key IXFPJGBNCFXKPI FSIHEZPIBRSMILES O C3O C H 2C 1 C C H OC O C C C C C H OC O CCCCCCC C H 1 C OC O C C C H OC O CCC C 2 O C 3 O C C CPropertiesChemical formula C 34H 50O 12Molar mass 650 762 g mol 1Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa N verify what is Y N Infobox references Thapsigargin raises cytosolic intracellular calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula Store depletion can secondarily activate plasma membrane calcium channels allowing an influx of calcium into the cytosol Depletion of ER calcium stores leads to ER stress and activation of the unfolded protein response 4 Non resolved ER stress can cumulatively lead to cell death 5 6 Prolonged store depletion can protect against ferroptosis via remodeling of ER synthesized phospholipids 7 Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR 8 9 Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations and ER calcium depletion A study from the University of Nottingham showed promising results for its use against Covid 19 and other coronavirus Contents 1 Biosynthesis 2 Research 3 See also 4 References 5 Further readingBiosynthesis EditThe complete biosynthesis of thapsigargin has yet to be elucidated A proposed biosynthesis starts with the farnesyl pyrophosphate The first step is controlled by the enzyme germacrene B synthase In the second step the C 8 position is easily activated for an allylic oxidation due to the position of the double bond The next step is the addition of the acyloxy moiety by a P450 acetyltransferase which is a well known reaction for the synthesis of the diterpene taxol In the third step the lactone ring is formed by a cytochrome P450 enzyme using NADP With the butyloxy group on the C 8 the formation will only generate the 6 12 lactone ring The fourth step is an epoxidation that initiates the last step of the base guaianolide formation In the fifth step a P450 enzyme closes the 5 7 guaianolide structure The ring closing is important because it will proceed via 1 10 epoxidation in order to retain the 4 5 double bond needed in thapsigargin It is not known whether the secondary modifications to the guaianolide occur before or after the formation of thapsigargin but will need to be considered when elucidating the true biosynthesis It should also be noted that several of these enzymes are P450s therefore oxygen and NADPH are likely crucial to this biosynthesis as well as other cofactors such as Mg2 and Mn2 may be needed 10 Research EditSince inhibition of SERCA is a mechanism of action that has been used to target solid tumors thapsigargin has attracted research interest A prodrug of thapsigargin mipsagargin is currently undergoing clinical trials for the treatment of glioblastoma 11 12 13 14 The biological activity has also attracted research into the laboratory synthesis of thapsigargin To date three distinct syntheses have been reported one by Steven V Ley 15 one by Phil Baran 16 and one by P Andrew Evans 17 Preclinical studies demonstrated that other effects of thapsigargin include suppression of nicotinic acetylcholine receptors activity in neurons of the guinea pig ileum submucous plexus 18 and rat superior cervical ganglion 19 Laboratory studies at the University of Nottingham using in vitro cell cultures indicates possible potential as a broad spectrum antiviral with activity against the COVID 19 virus SARS CoV 2 a common cold virus respiratory syncytial virus RSV and the influenza A virus 20 See also EditEBC 46References Edit Rogers TB Inesi G Wade R Lederer WJ 1995 Use of thapsigargin to study Ca2 homeostasis in cardiac cells Biosci Rep 15 5 341 9 doi 10 1007 BF01788366 PMID 8825036 S2CID 29613387 Rasmussen U Broogger Christensen S Sandberg F 1978 Thapsigargine and thapsigargicine two new histamine liberators from Thapsia garganica L Acta Pharm Suec 15 2 133 140 PMID 79299 a href wiki Template Cite journal title Template Cite journal cite journal a CS1 maint multiple names authors list link Hakii H Fujiki H Suganuma M Nakayasu M Tahira T Sugimura T Scheuer P J Christensen S B 1986 Thapsigargin a histamine secretagogue is a non 12 O tetradecanolphorbol 13 acetate TPA type tumor promoter in two stage mouse skin carcinogenesis Journal of Cancer Research and Clinical Oncology 111 3 177 181 doi 10 1007 BF00389230 PMID 2426275 S2CID 19093742 Malhotra Jyoti D Kaufman Randal J December 2007 The endoplasmic reticulum and the unfolded protein response Seminars in Cell amp Developmental Biology 18 6 716 731 doi 10 1016 j semcdb 2007 09 003 PMC 2706143 PMID 18023214 Hetz Claudio Papa Feroz R January 2018 The Unfolded Protein Response and Cell Fate Control Molecular Cell 69 2 169 181 doi 10 1016 j molcel 2017 06 017 PMID 29107536 Sano Renata Reed John C 2013 12 01 ER stress induced cell death mechanisms Biochimica et Biophysica Acta BBA Molecular Cell Research 1833 12 3460 3470 doi 10 1016 j bbamcr 2013 06 028 ISSN 0167 4889 PMC 3834229 PMID 23850759 Xin Shan Mueller Constanze Pfeiffer Susanne Kraft Vanessa A N Merl Pham Juliane Bao Xuanwen Feederle Regina Jin Xiang Hauck Stefanie M Schmitt Kopplin Philippe Schick Joel A 2021 10 18 MS4A15 drives ferroptosis resistance through calcium restricted lipid remodeling Cell Death amp Differentiation 29 3 670 686 doi 10 1038 s41418 021 00883 z ISSN 1476 5403 PMC 8901757 PMID 34663908 S2CID 239025829 Engedal Nikolai Torgersen Maria L Guldvik Ingrid J Barfeld Stefan J Bakula Daniela Saetre Frank Hagen Linda K Patterson John B Proikas Cezanne Tassula 2013 10 25 Modulation of intracellular calcium homeostasis blocks autophagosome formation Autophagy 9 10 1475 1490 doi 10 4161 auto 25900 ISSN 1554 8627 PMID 23970164 Ganley Ian G Wong Pui Mun Gammoh Noor Jiang Xuejun 2011 Distinct Autophagosomal Lysosomal Fusion Mechanism Revealed by Thapsigargin Induced Autophagy Arrest PDF Molecular Cell 42 6 731 743 doi 10 1016 j molcel 2011 04 024 PMC 3124681 PMID 21700220 Drew D P Krichau N Reichwald K Simonsen H T 2009 Guaianolides in apiaceae perspectives on pharmacology and biosynthesis Phytochem Rev 8 3 581 599 doi 10 1007 s11101 009 9130 z S2CID 37287410 Denmeade S R Mhaka A M Rosen D M Brennen W N Dalrymple S Dach I Olesen C Gurel B Demarzo A M Wilding G Carducci M A Dionne C A Moller J V Nissen P Christensen S B Isaacs J T 2012 Engineering a Prostate Specific Membrane Antigen Activated Tumor Endothelial Cell Prodrug for Cancer Therapy Science Translational Medicine 4 140 140ra86 doi 10 1126 scitranslmed 3003886 PMC 3715055 PMID 22745436 Andersen Trine Lopez Carmen Manczak Tom Martinez Karen Simonsen Henrik 2015 Thapsigargin From Thapsia L To Mipsagargin Molecules 20 4 6113 27 doi 10 3390 molecules20046113 PMC 6272310 PMID 25856061 Mipsagargin NCI Drug Dictionary National Cancer Institute 2011 02 02 Clinical Trials Mipsagargin National Cancer Institute 17 August 2017 Ball Matthew Andrews Stephen P Wierschem Frank Cleator Ed Smith Martin D Ley Steven V 2007 Total Synthesis of Thapsigargin a Potent SERCA Pump Inhibitor Organic Letters 9 4 663 6 doi 10 1021 ol062947x PMID 17256950 Chu Hang Smith Joel M Felding Jakob Baran Phil S 2017 Scalable Synthesis of Thapsigargin ACS Central Science 3 1 47 51 doi 10 1021 acscentsci 6b00313 PMC 5269647 PMID 28149952 Chen Dezhi Evans P Andrew 2017 A Concise Efficient and Scalable Total Synthesis of Thapsigargin and Nortrilobolide from R Carvone J Am Chem Soc 139 17 6046 6049 doi 10 1021 jacs 7b01734 PMID 28422492 Glushakov A V Glushakova H Y Skok V I 1999 01 15 Modulation of nicotinic acetylcholine receptor activity in submucous neurons by intracellular messengers Journal of the Autonomic Nervous System 75 1 16 22 doi 10 1016 S0165 1838 98 00165 9 ISSN 0165 1838 PMID 9935265 via https doi org 10 1016 S0165 1838 98 00165 9 a href wiki Template Cite journal title Template Cite journal cite journal a External link in code class cs1 code via code help Voitenko S V Bobryshev A Yu Skok V I 2000 01 01 Intracellular regulation of neuronal nicotinic cholinorceptors Neuroscience and Behavioral Physiology 30 1 19 25 doi 10 1007 BF02461388 ISSN 0097 0549 PMID 10768368 S2CID 10990124 Powerful Antiviral Treatment for COVID 19 Discovered That Could Change How Epidemics Are Managed 2 February 2021 lt 15 Dey S Bajaj S O Promising anticancer drug thapsigargin A perspective toward the total synthesis Synthetic communication 2018 48 1 1 13 gt Further reading EditDuncan G Wormstone IM Liu CS Marcantonio JM Davies PD September 1997 Thapsigargin coated intraocular lenses inhibit human lens cell growth Nat Med 3 9 1026 8 doi 10 1038 nm0997 1026 PMID 9288732 S2CID 6772670 Ibaraki N September 1997 A brighter future for cataract surgery Nat Med 3 9 958 60 doi 10 1038 nm0997 958 PMID 9288718 Retrieved from https en wikipedia org w index php title Thapsigargin amp oldid 1091301833, wikipedia, wiki, book,

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