Squalene

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Squalene
Skeletal formula of squalene
Spacefill model of squalene
Ball and stick model of squalene
Names
Preferred IUPAC name
(6E,10E,14E,18E)-2,6,10,15,19,23-Hexamethyltetracosa-2,6,10,14,18,22-hexaene[1]
Identifiers
3D model (JSmol)
3DMet
1728919
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.003.479 Edit this at Wikidata
EC Number
  • 203-826-1
KEGG
MeSH Squalene
RTECS number
  • XB6010000
UNII
  • InChI=1S/C30H50/c1-25(2)15-11-19-29(7)23-13-21-27(5)17-9-10-18-28(6)22-14-24-30(8)20-12-16-26(3)4/h15-18,23-24H,9-14,19-22H2,1-8H3/b27-17+,28-18+,29-23+,30-24+ checkY
    Key: YYGNTYWPHWGJRM-AAJYLUCBSA-N checkY
  • InChI=1/C30H50/c1-25(2)15-11-19-29(7)23-13-21-27(5)17-9-10-18-28(6)22-14-24-30(8)20-12-16-26(3)4/h15-18,23-24H,9-14,19-22H2,1-8H3
  • CC(=CCC/C(=C/CC/C(=C/CC/C=C(/CC/C=C(/CCC=C(C)C)\C)\C)/C)/C)C
Properties
C30H50
Molar mass 410.730 g·mol−1
Appearance Colourless oil
Density 0.858 g·cm−3
Melting point −5 °C (23 °F; 268 K)[3]
Boiling point 285 °C (545 °F; 558 K) at 3.3 kPa[2]
log P 12.188
Viscosity 12 cP (at 20 °C)
Hazards
NFPA 704 (fire diamond)
1
1
0
Flash point 110 °C (230 °F; 383 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Infobox references

Squalene is an organic compound. With the formula (C5H8)6, it is a triterpene. It is a colourless oil although impure samples appear yellow. It was originally obtained from shark liver oil (hence its name, as Squalus is a genus of sharks). All plants and animals produce squalene as a biochemical intermediate.[4] An estimated 12% of bodily squalene in humans comes from the sebum,[5] squalene has a role in topical skin lubrication and protection.[6]

Squalene is a precursor for synthesis of all plant and animal sterols, including cholesterol and steroid hormones in the human body.[7]

Squalene is an important ingredient in some vaccine adjuvants: Novartis produces a substance they call MF59, while GlaxoSmithKline produces AS03.

Role in steroid synthesis[edit]

Squalene is the biochemical precursor to steroids.[8] The squalene conversion begins with oxidation (via squalene monooxygenase) of one of its terminal double bonds, resulting in 2,3-oxidosqualene. It then undergoes an enzyme-catalysed cyclisation to produce lanosterol, which can be elaborated into other steroids such as cholesterol and ergosterol in a multistep process by the removal of three methyl groups, the reduction of one double bond by NADPH and the migration of the other double bond.

Squalene is an ancient molecule. In plants, squalene is the precursor to stigmasterol. In certain fungi, it is the precursor to ergosterol. However, blue-green algae and some bacteria do not produce squalene.[citation needed]

Production[edit]

Squalene is biosynthesised by coupling two molecules of farnesyl pyrophosphate. The condensation requires NADPH and the enzyme squalene synthase.

Cholesterol-Synthesis-Reaction10.png Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Squalene is prepared commercially from geranylacetone.[9]

Use as an adjuvant in vaccines[edit]

Immunologic adjuvants are substances, administered in conjunction with a vaccine, that stimulate the immune system and increase the response to the vaccine. Squalene is not itself an adjuvant, but it has been used in conjunction with surfactants in certain adjuvant formulations.[4]

An adjuvant using squalene is Seqirus' proprietary MF59, which is added to influenza vaccines to help stimulate the human body's immune response through production of CD4 memory cells. It is the first oil-in-water influenza vaccine adjuvant to be commercialised in combination with a seasonal influenza virus vaccine. It was developed in the 1990s by researchers at Ciba-Geigy and Chiron; both companies were subsequently acquired by Novartis.[4] Novartis was later acquired by CSL Bering and created the company Seqirus. It is present in the form of an emulsion and is added to make the vaccine more immunogenic.[4] However, the mechanism of action remains unknown. MF59 is capable of switching on a number of genes that partially overlap with those activated by other adjuvants.[10] How these changes are triggered is unclear; to date, no receptors responding to MF59 have been identified. One possibility is that MF59 affects the cell behaviour by changing the lipid metabolism, namely by inducing accumulation of neutral lipids within the target cells.[11] An influenza vaccine called FLUAD which used MF59 as an adjuvant was approved for use in the US in people 65 years of age and older, beginning with the 2016-2017 flu season.[12]

A 2009 meta-analysis assessed data from 64 clinical trials of influenza vaccines with the squalene-containing adjuvant MF59 and compared them to the effects of vaccines with no adjuvant. The analysis reported that the adjuvanted vaccines were associated with slightly lower risks of chronic diseases, but that neither type of vaccines altered the rate of autoimmune diseases; the authors concluded that their data "supports the good safety profile associated with MF59-adjuvanted influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines".[13]

Controversies[edit]

Attempts to link squalene to Gulf War Syndrome have been debunked.[14][15][16][17]

Shark conservation [edit]

In 2020, conservationists raised concerns about the potential slaughter of sharks to obtain squalene for a COVID-19 vaccine.[18]

Environmental and other concerns over shark hunting have motivated its extraction from other sources. Vegetable sources (primarily vegetable oils) include amaranth seed, rice bran, wheat germ, and olives.[19] Biosynthetic processes using genetically engineered yeast or bacteria is also used.[20][21]

Safety[edit]

Toxicology studies indicate that in the concentrations used in cosmetics, squalene has low acute toxicity, and is not a significant contact allergen or irritant.[22][23]

The World Health Organization and the US Department of Defense have both published extensive reports that emphasise that squalene is naturally occurring, even in oils of human fingerprints.[4][24] The WHO goes further to explain that squalene has been present in over 22 million flu vaccines given to patients in Europe since 1997 and there have never been significant vaccine-related adverse events.[4]

References[edit]

  1. ^ CID 1105 from PubChem
  2. ^ Merck Index, 11th Edition, 8727
  3. ^ Ernst, Josef; Sheldrick, William S.; Fuhrhop, Juergen H. (December 1976). "Crystal structure of squalene". Angewandte Chemie (in German). 88 (24): 851. doi:10.1002/ange.19760882414.
  4. ^ a b c d e f "Squalene-based adjuvants in vaccines". Global Advisory Committee on Vaccine Safety. World Health Organization. 21 July 2006.
  5. ^ Ronco, Alvaro L.; De Stéfani, Eduardo (20 December 2013). "Squalene: a multi-task link in the crossroads of cancer and aging". Functional Foods in Health and Disease. 3 (12): 462–476. doi:10.31989/ffhd.v3i12.30. ISSN 2160-3855.
  6. ^ Pappas, A (1 April 2009). "Epidermal surface lipids". Dermato-Endocrinology. Taylor & Francis. 1 (2): 72–76. doi:10.4161/derm.1.2.7811. PMC 2835894. PMID 20224687.
  7. ^ Micera, Marco; Botto, Alfonso; Geddo, Federica; Antoniotti, Susanna; Bertea, Cinzia Margherita; Levi, Renzo; Gallo, Maria Pia; Querio, Giulia (2 August 2020). "Squalene: More than a Step toward Sterols". Antioxidants. 9 (8): 688. doi:10.3390/antiox9080688. PMC 7464659. PMID 32748847.
  8. ^ Bloch, Konrad E. (1983). "Sterol, Structure and Membrane Function". Critical Reviews in Biochemistry and Molecular Biology. 14 (1): 47–92. doi:10.3109/10409238309102790. PMID 6340956.
  9. ^ Eggersdorfer, Manfred (15 June 2000). "Terpenes". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a26_205.
  10. ^ Mosca, Frank J.; Tritto, Elaine; Muzzi, Alessandro; Monaci, Ernesto; Bagnoli, Franco; Iavarone, Claudia; O'Hagan, Derek; Rappuoli, Rino; De Gregorio, Ennio (29 July 2008). "Molecular and cellular signatures of human vaccine adjuvants". Proceedings of the National Academy of Sciences. 105 (30): 10501–10506. Bibcode:2008PNAS..10510501M. doi:10.1073/pnas.0804699105. PMC 2483233. PMID 18650390.
  11. ^ Kalvodova, Lucie (12 March 2010). "Squalene-based oil-in-water emulsion adjuvants perturb metabolism of neutral lipids and enhance lipid droplet formation". Biochemical and Biophysical Research Communications. 393 (3): 350–355. doi:10.1016/j.bbrc.2009.12.062. PMID 20018176.
  12. ^ "FLUAD, Flu Vaccine With Adjuvant". Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases. 14 December 2017.
  13. ^ Pellegrini, Michele; Nicolay, Uwe; Lindert, Kelly; Groth, Nicola; Della Cioppa, Giovanni (16 November 2009). "MF59-adjuvanted versus non-adjuvanted influenza vaccines: Integrated analysis from a large safety database". Vaccine. 27 (49): 6959–6965. doi:10.1016/j.vaccine.2009.08.101. PMID 19751689.
  14. ^ Sox, Harold C.; Fulco, Carolyn; Liverman, Catharyn T. (2000). Gulf War and Health. National Academies Press. p. 311. ISBN 978-0-30907-178-9.
  15. ^ Del Giudice, Giuseppe; Fragapane, Elena; Bugarini, Roberto; Hora, Maninder; Henriksson, Thomas; Palla, Emanuela; O'Hagan, Derek; Donnelly, John; Rappuoli, Rino; Podda, Audino (7 September 2006). "Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene". Clinical and Vaccine Immunology. 13 (9): 1010–1013. doi:10.1128/CVI.00191-06. PMC 1563566. PMID 16960112.
  16. ^ "Gulf War illnesses: Questions About the Presence of Squalene Antibodies in Veterans Can Be Resolved" (PDF). U.S. Government Accountability Office. March 1999. Archived from the original (PDF) on 27 February 2021.
  17. ^ Jess Henig (18 Oct 2009). "FactCheck: Swine Flu Vaccine Fears Greatly Exaggerated". Newsweek.
  18. ^ Bowman, Emma (10 October 2020). "A Coronavirus Vaccine Could Kill Half A Million Sharks, Conservationists Warn". National Public Radio.
  19. ^ Wolosik, Katarzyna; Knaś, Małgorzata; Zalewska, Anna; Niczyporuk, Marek; Przystupa, Adrian Wojciech (30 November 2011). "The importance and perspective of plant-based squalene in cosmetology". Journal of Cosmetic Science. 64 (1): 59–65. PMID 23449131. S2CID 35333028.
  20. ^ Spanova, Miroslava; Daum, Günther (17 August 2011). "Squalene - biochemistry, molecular biology, process biotechnology, and applications". European Journal of Lipid Science and Technology. 113 (11): 1299–1320. doi:10.1002/ejlt.201100203.
  21. ^ Pan, Jian-Jung; Solbiati, Jose O.; Ramamoorthy, Gurusankar; Hillerich, Brandan S.; Seidel, Ronald D.; Cronan, John E.; Almo, Steven C.; Poulter, C. Dale (20 April 2015). "Biosynthesis of Squalene from Farnesyl Diphosphate in Bacteria: Three Steps Catalysed by Three Enzymes". ACS Central Science. 1 (2): 77–82. doi:10.1021/acscentsci.5b00115. PMC 4527182. PMID 26258173.
  22. ^ "Final Report on the Safety Assessment of Squalane and Squalene" (PDF). International Journal of Toxicology. 1 (2): 37–56. 1982. doi:10.3109/10915818209013146. S2CID 31454284.
  23. ^ Huang, Zih-Rou; Lin, Yin-Ku; Fang, Jia-You (16 November 2009). "Biological and Pharmacological Activities of Squalene and Related Compounds: Potential Uses in Cosmetic Dermatology" (PDF). Molecules. 14 (1): 540–554. doi:10.3390/molecules14010540. PMC 6253993. PMID 19169201.
  24. ^ Asano, Keiji G.; Bayne, Charles K.; Horsman, Katie M.; Buchanan, Michelle V. (17 January 2002). "Chemical Composition of Fingerprints for Gender Determination". Journal of Forensic Sciences. 47 (4): 805–807. doi:10.1520/JFS15460J. PMID 12136987.

External links[edit]