Thapsigargin

Thapsigargin
Names
IUPAC name
(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-(acetyloxy)-4-(butyryloxy)-3,3a-dihydroxy-3,6,9-trimethyl-8-{[(2Z)-2-methylbut-2-enoyl]oxy}-2-oxo-2,3,3a,4,5,6,6a,7,8,9b-decahydroazuleno[4,5-b]furan-7-yl octanoate
Identifiers
67526-95-8 
ChEBI CHEBI:9516 Yes
ChEMBL ChEMBL96926 
ChemSpider 393753 Yes
Jmol-3D images Image
PubChem 446378
Properties
Molecular formula
 C34H50O12
Molar mass 650.75 g·mol−1
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
  verify (what is: Yes/?)
Infobox references

Thapsigargin is non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA).[1] Structurally, thapsigargin is classified as a sesquiterpene lactone, and is extracted from a plant, Thapsia garganica. It is a tumor promoter in mammalian cells.[2] The anti-malarial drug artemisinin is also a sesquiterpene lactone, leading to a proposal that this class of drugs works by inhibiting the SERCA of malaria parasites such as Plasmodium falciparum;[3][4] this hypothesis awaits confirmation.[5]

Thapsigargin raises cytosolic (intracellular) calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula which causes these stores to become depleted. Store-depletion can secondarily activate plasma membrane calcium channels, allowing an influx of calcium into the cytosol.

Thapsigargin specifically inhibits the fusion of autophagosomes with lysosomes; the last step in the autophagic process. The inhibition of the autophagic process in turn induces stress on the endoplasmic reticulum which ultimately leads to cellular death.[6]

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

Potential medical uses of thapsigargin

Thapsigargin is mentioned as a possible treatment for posterior capsular opacification.

Biosynthesis

The complete biosynthesis of thapsigargin has yet to be elucidated. A proposed biosynthetic pathway is shown below. The biosynthesis starts with the common terpene farnesyl pyrophosphate. The first step, I, is controlled by the enzyme germacrene B synthase. For step II, 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 step III, 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. Step IV is an epoxidation that initiates the last step of the base guaianolide formation. In step V, 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 P450's, therefore oxygen and NADPH are likely crucial to this biosynthesis as well as other cofactors such as Mg2+ and Mn2+ may be needed.[7]

See also

References

  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.
  2. ↑ 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.
  3. ↑ Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, O'Neill PM, Bray PG, Ward SA, Krishna S (August 2003). "Artemisinins target the SERCA of Plasmodium falciparum". Nature 424 (6951): 957–61. doi:10.1038/nature01813. PMID 12931192.
  4. ↑ Golenser J, Waknine JH, Krugliak M, Hunt NH, Grau GE (2006). "Current perspectives on the mechanism of action of artemisinins". Int. J. Parasitol. 36 (14): 1427–41. doi:10.1016/j.ijpara.2006.07.011. PMID 17005183.
  5. ↑ Eastman RT, Fidock DA (December 2009). "Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria". Nat. Rev. Microbiol. 7 (12): 864–74. doi:10.1038/nrmicro2239. PMC 2901398. PMID 19881520.
  6. ↑ Ganley, Ian G.; Wong, Pui-Mun; Gammoh, Noor; Jiang, Xuejun "Distinct Autophagosomal-Lysosomal Fusion Mechanism Revealed by Thapsigargin-Induced Autophagy Arrest" Molecular cell doi:10.1016/j.molcel.2011.04.024 (volume 42 issue 6 pp.731 - 743)
  7. ↑ 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.

Further reading

External links