{{Distinguish|squalane}} {{Chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 460767124 | ImageFile = Squalene.svg | ImageFile_Ref = {{chemboximage|correct|??}} | ImageSize = 244 | ImageName = Skeletal formula of squalene | ImageFile1 = Squalene-from-xtal-3D-vdW-A.png | ImageFile1_Ref = {{chemboximage|correct|??}} | ImageSize1 = 244 | ImageName1 = Spacefill model of squalene | ImageFile2 = Squalene-from-xtal-3D-balls-A.png | ImageFile2_Ref = {{chemboximage|correct|??}} | ImageSize2 = 244 | ImageName2 = Ball and stick model of squalene | PIN = (6''E'',10''E'',14''E'',18''E'')-2,6,10,15,19,23-Hexamethyltetracosa-2,6,10,14,18,22-hexaene<ref>{{PubChem|1105}}</ref> | Section1 = {{Chembox Identifiers | IUPHAR_ligand = 3054 | CASNo = 111-02-4 | CASNo_Ref = {{cascite|correct|CAS}} | PubChem = 638072 | ChemSpiderID = 553635 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | UNII = 7QWM220FJH | UNII_Ref = {{fdacite|correct|FDA}} | EINECS = 203-826-1 | KEGG = C00751 | KEGG_Ref = {{keggcite|changed|kegg}} | MeSHName = Squalene | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 15440 | ChEMBL = 458402 | ChEMBL_Ref = {{ebicite|correct|EBI}} | RTECS = XB6010000 | Beilstein = 1728919 | 3DMet = B00166 | SMILES = CC(=CCC/C(=C/CC/C(=C/CC/C=C(/CC/C=C(/CCC=C(C)C)\C)\C)/C)/C)C | StdInChI = 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+ | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | 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 | StdInChIKey = YYGNTYWPHWGJRM-AAJYLUCBSA-N | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} }} | Section2 = {{Chembox Properties | C=30 | H=50 | Appearance = Colourless oil | Density = 0.858{{nbsp}}g·cm<sup>−3</sup> | MeltingPtC = -5 | MeltingPt_ref = <ref>{{cite journal |author1=Ernst, Josef |author2=Sheldrick, William S. |author3=Fuhrhop, Juergen H. |date=December 1976 |title=Crystal structure of squalene |journal=Angewandte Chemie |language=de |volume=88 |issue=24 |pages=851 |doi=10.1002/ange.19760882414}}</ref> | BoilingPtC = 285 | BoilingPt_notes = at 3.3&nbsp;kPa<ref>''Merck Index'', 11th Edition, '''8727'''</ref> | LogP = 12.188 | Viscosity = 12{{nbsp}}cP (at 20&nbsp;°C) | RefractIndex = 1.4956 (at 20&nbsp;°C) <ref>{{cite journal |author1=Pabst, Florian |author2=Blochowicz, Thomas |date=December 2022 |title=On the intensity of light scattered by molecular liquids - Comparison of experiment and quantum chemical calculations |journal=The Journal of Chemical Physics |language=en |volume=157 |issue=24 |pages=244501 |bibcode=2022JChPh.157x4501P |doi=10.1063/5.0133511 |pmid=36586992 |s2cid=255032687 |doi-access=free}}</ref> }} | Section3 = {{Chembox Hazards | FlashPtC = 110 | NFPA-H= 1 | NFPA-F= 1 | NFPA-R= 0 }} }}

'''Squalene''' is an organic compound. It is a triterpene with the formula C<sub>30</sub>H<sub>50</sub>. 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). An estimated 12% of bodily squalene in humans is found in sebum.<ref>{{cite journal |last1=Ronco |first1=Alvaro L. |last2=De Stéfani |first2=Eduardo |date=20 December 2013 |title=Squalene: a multi-task link in the crossroads of cancer and aging |url=https://ffhdj.com/index.php/ffhd/article/view/30 |journal=Functional Foods in Health and Disease |volume=3 |issue=12 |pages=462–476 |doi=10.31989/ffhd.v3i12.30 |issn=2160-3855 |doi-access=free}}</ref> Squalene has a role in topical skin lubrication and protection.<ref>{{cite journal |last=Pappas |first=A |date=1 April 2009 |title=Epidermal surface lipids |journal=Dermato-Endocrinology |publisher=Taylor & Francis |volume=1 |issue=2 |pages=72–76 |doi=10.4161/derm.1.2.7811 |pmc=2835894 |pmid=20224687}}</ref>

Most plants, fungi, and animals produce squalene as biochemical precursor in sterol biosynthesis, including cholesterol and steroid hormones in the human body.<ref>{{cite journal |last1=Micera |first1=Marco |last2=Botto |first2=Alfonso |last3=Geddo |first3=Federica |last4=Antoniotti |first4=Susanna |last5=Bertea |first5=Cinzia Margherita |last6=Levi |first6=Renzo |last7=Gallo |first7=Maria Pia |last8=Querio |first8=Giulia |date=2 August 2020 |title=Squalene: More than a Step toward Sterols |journal=Antioxidants |volume=9 |issue=8 |page=688 |doi=10.3390/antiox9080688 |pmc=7464659 |pmid=32748847 |doi-access=free}}</ref><ref name="Cholesterol Biosynthesis: A Mechani">{{cite journal |last1=Cerqueira |first1=Nuno M. F. S. A. |last2=Oliveira |first2=Eduardo F. |last3=Gesto |first3=Diana S. |last4=Santos-Martins |first4=Diogo |last5=Moreira |first5=Cátia |last6=Moorthy |first6=Hari N. |last7=Ramos |first7=Maria J. |last8=Fernandes |first8=P. A. |date=4 October 2016 |title=Cholesterol Biosynthesis: A Mechanistic Overview |journal=Biochemistry |volume=55 |issue=39 |pages=5483–5506 |doi=10.1021/acs.biochem.6b00342 |pmid=27604037}}</ref><ref>{{cite journal |last1=ZANDEE |first1=DI |date=27 June 1964 |title=Absence of Sterol Synthesis in some Arthropods |journal=Nature |volume=202 |issue=4939 |pages=1335–6 |bibcode=1964Natur.202.1335Z |doi=10.1038/2021335a0 |pmid=14210972 |s2cid=4221673}}</ref> It is also an intermediate in the biosynthesis of hopanoids in many bacteria.<ref>{{cite journal |last1=Abe |first1=Ikuro |date=2007 |title=Enzymatic synthesis of cyclic triterpenes |journal=Natural Product Reports |volume=24 |issue=6 |pages=1311–1331 |doi=10.1039/b616857b |pmid=18033581}}</ref>

Squalene is an important ingredient in some vaccine adjuvants: The Novartis and GlaxoSmithKline adjuvants are called MF59 and AS03, respectively.<ref name="who.int">{{cite news |date=21 July 2006 |title=Squalene-based adjuvants in vaccines |url=https://www.who.int/vaccine_safety/committee/topics/adjuvants/squalene/questions_and_answers/en/ |url-status=dead |archive-url=https://web.archive.org/web/20121104105400/http://www.who.int/vaccine_safety/committee/topics/adjuvants/squalene/questions_and_answers/en/ |archive-date=November 4, 2012 |work=Global Advisory Committee on Vaccine Safety |publisher=World Health Organization}}</ref>

==Role in triterpenoid synthesis== Squalene is a biochemical precursor to both steroids and hopanoids.<ref>{{cite journal |last=Bloch |first=Konrad E. |year=1983 |title=Sterol, Structure and Membrane Function |journal=Critical Reviews in Biochemistry and Molecular Biology |volume=14 |issue=1 |pages=47–92 |doi=10.3109/10409238309102790 |pmid=6340956}}</ref> For sterols, 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.<ref name="Cholesterol Biosynthesis: A Mechani"/> In many plants, this is then converted into stigmasterol, while in many fungi, it is the precursor to ergosterol.{{citation needed|date=July 2023}} {{clear|left}}

The biosynthetic pathway is found in many bacteria,<ref>{{cite journal |last1=Rohmer |first1=M. |last2=Bouvier-Nave |first2=P. |last3=Ourisson |first3=G. |date=1 May 1984 |title=Distribution of Hopanoid Triterpenes in Prokaryotes |journal=Microbiology |volume=130 |issue=5 |pages=1137–1150 |doi=10.1099/00221287-130-5-1137 |doi-access=free}}</ref> and most eukaryotes, though has not been found in Archaea.<ref>{{cite journal |last1=Santana-Molina |first1=Carlos |last2=Rivas-Marin |first2=Elena |last3=Rojas |first3=Ana M |last4=Devos |first4=Damien P |date=1 July 2020 |title=Origin and Evolution of Polycyclic Triterpene Synthesis |journal=Molecular Biology and Evolution |volume=37 |issue=7 |pages=1925–1941 |doi=10.1093/molbev/msaa054 |pmc=7306690 |pmid=32125435}}</ref>

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

700px {{StatinPathway_WP430|highlight=Squalene}}

===Industry=== {{missing information|section|all routes currently used; market share of each|date=January 2022}} Synthetic squalene is prepared commercially from geranylacetone.<ref>{{Ullmann|last1=Eggersdorfer|first1=Manfred|title=Terpenes|date=15 June 2000|doi=10.1002/14356007.a26_205}}</ref>

===Shark conservation {{anchor|Shark squalene}}=== In 2020, conservationists raised concerns about the potential slaughter of sharks to obtain squalene for a COVID-19 vaccine.<ref>{{cite web |last=Bowman |first=Emma |date=10 October 2020 |title=A Coronavirus Vaccine Could Kill Half A Million Sharks, Conservationists Warn |url=https://www.npr.org/sections/coronavirus-live-updates/2020/10/10/922398246/a-coronavirus-vaccine-could-kill-half-a-million-sharks-conservationists-warn |website=National Public Radio}}</ref>

Environmental and other concerns over shark hunting have motivated its extraction from other sources.<ref>{{Cite journal |last1=Mendes |first1=Adélia |last2=Azevedo-Silva |first2=João |last3=Fernandes |first3=João C. |date=2022-02-22 |title=From Sharks to Yeasts: Squalene in the Development of Vaccine Adjuvants |journal=Pharmaceuticals |volume=15 |issue=3 |pages=265 |doi=10.3390/ph15030265 |issn=1424-8247 |pmc=8951290 |pmid=35337064 |doi-access=free}}</ref> Biosynthetic processes use genetically engineered yeast or bacteria.<ref>{{cite journal |last1=Spanova |first1=Miroslava |last2=Daum |first2=Günther |date=17 August 2011 |title=Squalene – biochemistry, molecular biology, process biotechnology, and applications |journal=European Journal of Lipid Science and Technology |volume=113 |issue=11 |pages=1299–1320 |doi=10.1002/ejlt.201100203}}</ref><ref>{{cite journal |last1=Pan |first1=Jian-Jung |last2=Solbiati |first2=Jose O. |last3=Ramamoorthy |first3=Gurusankar |last4=Hillerich |first4=Brandan S. |last5=Seidel |first5=Ronald D. |last6=Cronan |first6=John E. |last7=Almo |first7=Steven C. |last8=Poulter |first8=C. Dale |date=20 April 2015 |title=Biosynthesis of Squalene from Farnesyl Diphosphate in Bacteria: Three Steps Catalysed by Three Enzymes |journal=ACS Central Science |volume=1 |issue=2 |pages=77–82 |doi=10.1021/acscentsci.5b00115 |doi-access=free|pmc=4527182 |pmid=26258173}}</ref>

==Uses== ===As an adjuvant in vaccines=== {{see also|AS03|MF59}} 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.<ref name=who.int/>

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.<ref name=who.int/> The Influenza vaccine business of Novartis was later acquired by CSL Bering and created the company Seqirus.<ref>{{Cite web |last=Philippidis |first=Alex |date=2014-10-27 |title=Novartis Selling Flu Vaccine Business to CSL for $275M |url=https://www.genengnews.com/news/novartis-selling-flu-vaccine-business-to-csl-for-275m/ |access-date=2024-09-16 |website=GEN - Genetic Engineering and Biotechnology News |language=en-US}}</ref> It is present in the form of an emulsion and is added to make the vaccine more immunogenic.<ref name=who.int/> 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.<ref>{{cite journal |last1=Mosca |first1=Frank J. |last2=Tritto |first2=Elaine |last3=Muzzi |first3=Alessandro |last4=Monaci |first4=Ernesto |last5=Bagnoli |first5=Franco |last6=Iavarone |first6=Claudia |last7=O'Hagan |first7=Derek |last8=Rappuoli |first8=Rino |last9=De Gregorio |first9=Ennio |date=29 July 2008 |title=Molecular and cellular signatures of human vaccine adjuvants |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=30 |pages=10501–10506 |bibcode=2008PNAS..10510501M |doi=10.1073/pnas.0804699105 |pmc=2483233 |pmid=18650390 |doi-access=free}}</ref> 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.<ref>{{cite journal |last=Kalvodova |first=Lucie |date=12 March 2010 |title=Squalene-based oil-in-water emulsion adjuvants perturb metabolism of neutral lipids and enhance lipid droplet formation |journal=Biochemical and Biophysical Research Communications |volume=393 |issue=3 |pages=350–355 |bibcode=2010BBRC..393..350K |doi=10.1016/j.bbrc.2009.12.062 |pmid=20018176}}</ref> An influenza vaccine called [https://www.fluad.ca/patient/en/index.html?gclid=Cj0KCQiAzMGNBhCyARIsANpUkzPPnohR9VXZ2WLu-FjLHTTuYljtqZti7Qybbq-nr59zQ3gcvSBUwlwaAng1EALw_wcB 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.<ref>{{cite web |date=14 December 2017 |title=FLUAD, Flu Vaccine With Adjuvant |url=https://www.cdc.gov/flu/protect/vaccine/adjuvant.htm |publisher=Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases}}</ref>

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 adjuvated 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-adjuvated influenza vaccines and suggests there may be a clinical benefit over non-MF59-containing vaccines".<ref>{{cite journal |last1=Pellegrini |first1=Michele |last2=Nicolay |first2=Uwe |last3=Lindert |first3=Kelly |last4=Groth |first4=Nicola |last5=Della Cioppa |first5=Giovanni |date=16 November 2009 |title=MF59-adjuvated versus non-adjuvated influenza vaccines: Integrated analysis from a large safety database |journal=Vaccine |volume=27 |issue=49 |pages=6959–6965 |doi=10.1016/j.vaccine.2009.08.101 |pmid=19751689}}</ref>

==Safety== Toxicology studies indicate that in the concentrations used in cosmetics, squalene has low acute toxicity, and is not a significant contact allergen or irritant.<ref>{{cite journal |year=1982 |title=Final Report on the Safety Assessment of Squalane and Squalene |url=http://www.beauty-review.nl/wp-content/uploads/2014/08/Final-Report-on-the-Safety-Assessment-of-Squalane-and-Squalene.pdf |journal=International Journal of Toxicology |volume=1 |issue=2 |pages=37–56 |doi=10.3109/10915818209013146 |s2cid=31454284}}</ref><ref>{{cite journal |last1=Huang |first1=Zih-Rou |last2=Lin |first2=Yin-Ku |last3=Fang |first3=Jia-You |date=16 November 2009 |title=Biological and Pharmacological Activities of Squalene and Related Compounds: Potential Uses in Cosmetic Dermatology |url=http://skinbio.com/squalene-skin.pdf |journal=Molecules |volume=14 |issue=1 |pages=540–554 |doi=10.3390/molecules14010540 |pmc=6253993 |pmid=19169201 |doi-access=free}}</ref>

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.<ref name=who.int/><ref>{{cite journal |last1=Asano |first1=Keiji G. |last2=Bayne |first2=Charles K. |last3=Horsman |first3=Katie M. |last4=Buchanan |first4=Michelle V. |date=17 January 2002 |title=Chemical Composition of Fingerprints for Gender Determination |journal=Journal of Forensic Sciences |volume=47 |issue=4 |pages=805–807 |doi=10.1520/JFS15460J |pmid=12136987}}</ref> The WHO goes further to explain that squalene has been present in over 22 million flu vaccines given to patients in Europe since 1997 without significant vaccine-related adverse events.<ref name=who.int/>

===Controversies=== There have been attempts to link squalene to Gulf War syndrome, but these have been debunked, and it was later revealed that squalene was not an ingredient of the vaccines in question.<ref>{{cite book |last1=Sox |first1=Harold C. |url=https://archive.org/details/gulfwarhealth00fulc |title=Gulf War and Health |last2=Fulco |first2=Carolyn |last3=Liverman |first3=Catharyn T. |publisher=National Academies Press |year=2000 |isbn=978-0-30907-178-9 |page=[https://archive.org/details/gulfwarhealth00fulc/page/311 311] |url-access=registration}}</ref><ref>{{cite journal |last1=Del Giudice |first1=Giuseppe |last2=Fragapane |first2=Elena |last3=Bugarini |first3=Roberto |last4=Hora |first4=Maninder |last5=Henriksson |first5=Thomas |last6=Palla |first6=Emanuela |last7=O'Hagan |first7=Derek |last8=Donnelly |first8=John |last9=Rappuoli |first9=Rino |last10=Podda |first10=Audino |date=7 September 2006 |title=Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene |journal=Clinical and Vaccine Immunology |volume=13 |issue=9 |pages=1010–1013 |doi=10.1128/CVI.00191-06 |pmc=1563566 |pmid=16960112}}</ref><ref>{{cite web |date=March 1999 |title=Gulf War illnesses: Questions About the Presence of Squalene Antibodies in Veterans Can Be Resolved |url=https://www.gao.gov/archive/1999/ns99005.pdf |url-status=dead |archive-url=https://web.archive.org/web/20210227012900/https://www.gao.gov/archive/1999/ns99005.pdf |archive-date=27 February 2021 |publisher=U.S. Government Accountability Office}}</ref><ref>{{cite news |last=Henig |first=Jess |date=18 October 2009 |title=FactCheck: Swine Flu Vaccine Fears Greatly Exaggerated |url=https://www.newsweek.com/factcheck-swine-flu-vaccine-fears-greatly-exaggerated-81069 |work=Newsweek}}</ref>

==References== {{Reflist|30em}}

==External links== * [http://gmd.mpimp-golm.mpg.de/Spectrums/59c189cc-87aa-4547-8914-4bf3df9d5f5b.aspx Squalene MS Spectrum]

{{Cholesterol metabolism intermediates}} {{Terpenoids}}

Category:Chemical synthesis Category:Chemical processes Category:Toxicology Category:Polyenes Category:Biomolecules Category:Steroid hormone biosynthesis Category:Hydrocarbons Category:Triterpenes Category:Vaccination Category:Tree-derived bioactive compounds