Squalene
Skeletal formula of squalene
Spacefill model of squalene
Ball and stick model of squalene
Names
Systematic 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
Properties
C30H50
Molar mass 410.730 g·mol−1
Appearance colorless 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)
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored 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 colorless oil although impure samples appear yellow. It 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 coming 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 conversion begins with oxidation (via squalene monooxygenase) of one of the terminal double bonds of squalene. The resulting 2,3-squalene oxide undergoes enzyme-catalyzed cyclization to afford lanosterol, which is then elaborated into cholesterol and other steroids.

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 manufacture squalene.[citation needed]

Production[edit]

Squalene is biosynthesized 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.[10]

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 commercialized 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.[10] 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.[10] 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.[11] 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 behavior by changing the lipid metabolism, namely by inducing accumulation of neutral lipids within the target cells.[12] 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.[13]

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".[14]

Controversies[edit]

Attempts to link squalene to Gulf War Syndrome have been debunked.[15][16][17][18]

Shark conservation [edit]

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

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.[20] Biosynthetic processes using genetically engineered yeast or bacteria is also used.[21][22]

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.[23][24][25]

The World Health Organization and the US Department of Defense have both published extensive reports that emphasize that squalene is naturally occurring, even in oils of human fingerprints.[10][26] 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.[10]

References[edit]

  1. ^ CID 1105 from PubChem
  2. ^ Merck Index, 11th Edition, 8727
  3. ^ Ernst, Josef; Sheldrick, William S.; Fuhrhop, Juergen H. (1976). "Crystal structure of squalene". Angewandte Chemie. 88 (24): 851. doi:10.1002/ange.19760882414.
  4. ^ "Squalene-based adjuvants in vaccines". World Health Organization. 21 July 2006.
  5. ^ Ronco, Alvaro L.; Stéfani, Eduardo De (2013-12-20). "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 (2009). "Epidermal surface lipids". Dermato-endocrinology. 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 (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 Functio". Critical Reviews in Biochemistry and Molecular Biology. 14 (1): 47–92. doi:10.3109/10409238309102790. PMID 6340956.
  9. ^ Eggersdorfer, Manfred (2000). "Terpenes". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a26_205.
  10. ^ a b c d e Squalene-based adjuvants in vaccines, Global Advisory Committee on Vaccine Safety, World Health Organization
  11. ^ Mosca, F.; Tritto, E.; Muzzi, A.; Monaci, E.; Bagnoli, F.; Iavarone, C.; O'Hagan, D.; Rappuoli, R.; De Gregorio, E. (2008). "Molecular and cellular signatures of human vaccine adjuvants". Proceedings of the National Academy of Sciences. 105 (30): 10501–6. Bibcode:2008PNAS..10510501M. doi:10.1073/pnas.0804699105. PMC 2483233. PMID 18650390.
  12. ^ Kalvodova, Lucie (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): 350–5. doi:10.1016/j.bbrc.2009.12.062. PMID 20018176.
  13. ^ "FLUAD, Flu Vaccine With Adjuvant". US Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases. 14 December 2017.
  14. ^ Pellegrini, Michele; Nicolay, Uwe; Lindert, Kelly; Groth, Nicola; Della Cioppa, Giovanni (2009). "MF59-adjuvanted versus non-adjuvanted influenza vaccines: Integrated analysis from a large safety database". Vaccine. 27 (49): 6959–65. doi:10.1016/j.vaccine.2009.08.101. PMID 19751689.
  15. ^ Sox, Harold C.; Fulco, Carolyn; Liverman, Catharyn T. (2000). Gulf War and health. Washington, D.C: National Academy Press. p. 311. ISBN 978-0-309-07178-9.
  16. ^ Del Giudice, G.; Fragapane, E.; Bugarini, R.; Hora, M.; Henriksson, T.; Palla, E.; O'Hagan, D.; Donnelly, J.; et al. (2006). "Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene". Clinical and Vaccine Immunology. 13 (9): 1010–3. doi:10.1128/CVI.00191-06. PMC 1563566. PMID 16960112.
  17. ^ Gulf War illnesses: questions about the presence of squalene antibodies in veterans can be resolved, United States General Accounting Office 1999
  18. ^ Jess Henig Innoculation Misinformation: Claims that the swine flu vaccine is dangerous range from overblown to false Newsweek Oct 19, 2009
  19. ^ Bowman, Emma (October 10, 2020). "A Coronavirus Vaccine Could Kill Half A Million Sharks, Conservationists Warn". NPR.
  20. ^ Wolosik K1, Knas M, Zalewska A, Niczyporuk M, Przystupa AW. The importance and perspective of plant-based squalene in cosmetology. J Cosmet Sci. 2013 Jan-Feb;64(1):59-66.
  21. ^ Spanova, Miroslava & Daum, Guenther. Squalene - biochemistry, molecular biology, process biotechnology, and applications. Eur. J. Lipid Sci. Technol. 2011,000, 0000–0000 DOI:10.1002/ejlt.201100203
  22. ^ Biosynthesis of Squalene from Farnesyl Diphosphate in Bacteria: Three Steps Catalyzed by Three Enzymes. Jian-Jung Pan, Jose O. Solbiati, Gurusankar Ramamoorthy, Brandan S. Hillerich, Ronald D. Seidel, John E. Cronan, Steven C. Almo, and C. Dale Poulter. ACS Central Science 2015 1 (2), 77-82 DOI: 10.1021/acscentsci.5b00115
  23. ^ "Final Report on the Safety Assessment of Squalane and Squalene". International Journal of Toxicology. 1 (2): 37–56. 1982. doi:10.3109/10915818209013146. S2CID 31454284.
  24. ^ "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.
  25. ^ Huang, Zih-Rou; Lin, Yin-Ku; Fang, Jia-You (2009). "Biological and Pharmacological Activities of Squalene and Related Compounds: Potential Uses in Cosmetic Dermatology" (PDF). Molecules. 14 (1): 540–54. doi:10.3390/molecules14010540. PMC 6253993. PMID 19169201.
  26. ^ Asano, KG; Bayne, CK; Horsman, KM; Buchanan, MV (2002). "Chemical composition of fingerprints for gender determination". Journal of Forensic Sciences. 47 (4): 805–7. doi:10.1520/JFS15460J. PMID 12136987.

External links[edit]