Fatty acid desaturase

{{Infobox protein family |Symbol = Fatty_acid_desaturase-1 |Name = Fatty acid desaturase, type 1 |Pfam = PF00487 |InterPro = IPR005804 |PROSITE = |OPM family = 431| OPM protein =4zyo |PDB = }} {{Infobox protein family |Symbol = Fatty_acid_desaturase-2 |Name = Fatty acid desaturase, type 2 |Pfam = PF03405 |InterPro = IPR005067 |PROSITE = |PDB = }}

'''Fatty acid desaturases''' (also called unsaturases) are a family of enzymes that convert saturated fatty acids into unsaturated fatty acids and polyunsaturated fatty acids. For the common fatty acids of the C18 variety, desaturases convert stearic acid into oleic acid. Other desaturases convert oleic acid into linoleic acid, which is the precursor to alpha-linolenic acid, gamma-linolenic acid, and eicosatrienoic acid.<ref>{{cite journal | vauthors = Jiao J, Zhang Y | title = Transgenic biosynthesis of polyunsaturated fatty acids: a sustainable biochemical engineering approach for making essential fatty acids in plants and animals | journal = Chemical Reviews | volume = 113 | issue = 5 | pages = 3799–3814 | date = May 2013 | pmid = 23421688 | doi = 10.1021/cr300007p }}</ref>

Two nomenclatures are used to indicate the position of desaturation: * Delta - indicating that the double bond is created at a fixed position from the carboxyl end of a fatty acid chain. For example, Δ9-desaturase creates a double bond between the ninth and tenth carbon atom from the carboxyl end. * Omega - indicating the double bond is created at a fixed position from the methyl end of a fatty acid chain. For instance, ω3 desaturase creates a double bond between the third and fourth carbon atom from the methyl end. In other words, it creates an omega-3 fatty acid.

For example, Δ6 desaturation introduces a double bond between carbons 6 and 7 of linoleic acid (LA C18H32O2; 18:2-n6) and α-linolenic acid (ALA: C18H30O2; 18:3-n3), creating ''γ''-linolenic acid (GLA: C18H30O2,18:3-n6) and stearidonic acid (SDA: C18H28O2; 18:4-n3) respectively.<ref name=":2">{{cite journal | vauthors = Abedi E, Sahari MA | title = Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties | journal = Food Science & Nutrition | volume = 2 | issue = 5 | pages = 443–463 | date = September 2014 | pmid = 25473503 | pmc = 4237475 | doi = 10.1002/fsn3.121 }}</ref>

In the biosynthesis of essential fatty acids, an elongase alternates with various desaturases (for example, Δ6-desaturase) to create larger molecules. The elongase extends the molecule by two methylene groups (-CH2-CH2-) while the desaturase forms double bonds.

==Classification== Δ-desaturases are represented by two distinct families which do not seem to be evolutionarily related.

Family 1 uses cytochrome b5 as the electron donor. This family includes all animal and fungal fatty acid desaturases, including the human types listed below.<ref name="PUB00002505">{{cite journal | vauthors = Kaestner KH, Ntambi JM, Kelly Jr TJ, Lane MD | title = Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA desaturase | journal = The Journal of Biological Chemistry | volume = 264 | issue = 25 | pages = 14755–61 | date = September 1989 | doi = 10.1016/S0021-9258(18)63763-9 | pmid = 2570068 | url = https://www.jbc.org/content/264/25/14755.full.pdf | doi-access = free }}</ref> This type is also found in plants and bacteria. Desaturases of this family are largely membrane-bound. They process acyl-CoA and acyl-lipid substrates.<ref name=pmid36017969>{{cite journal |last1=Cerone |first1=M |last2=Smith |first2=TK |title=Desaturases: Structural and mechanistic insights into the biosynthesis of unsaturated fatty acids. |journal=IUBMB Life |date=November 2022 |volume=74 |issue=11 |pages=1036–1051 |doi=10.1002/iub.2671 |pmid=36017969 |pmc=9825965}}</ref> The Pfam domain (PF00487) also matches the closely related alkane 1-monooxygenases, a reflection of the catalytic flexibility of the FADS-like superfamily. The sphingolipid α-hydroxylases also belong to the same superfamily.<ref>{{cite journal |last1=Guo |first1=X |last2=Zhang |first2=J |last3=Han |first3=L |last4=Lee |first4=J |last5=Williams |first5=SC |last6=Forsberg |first6=A |last7=Xu |first7=Y |last8=Austin |first8=RN |last9=Feng |first9=L |title=Structure and mechanism of the alkane-oxidizing enzyme AlkB. |journal=Nature Communications |date=17 April 2023 |volume=14 |issue=1 |pages=2180 |doi=10.1038/s41467-023-37869-z |pmid=37069165 |pmc=10110569 |bibcode=2023NatCo..14.2180G }}</ref>

Family 2 uses ferredoxin as the electron donor. This family is found in bacteria and plant plastids. Desaturases of this family are largely soluble and process acyl‐lipid and acyl‐ACP (acyl carrier protein) substrates.<ref name=pmid36017969/> Notable examples include: * Plant stearoyl-(acyl-carrier-protein) 9-desaturase ({{EC number|1.14.19.2}}),<ref name="PUB00004734">{{cite journal | vauthors = Shanklin J, Somerville C | title = Stearoyl-acyl-carrier-protein desaturase from higher plants is structurally unrelated to the animal and fungal homologs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 6 | pages = 2510–4 | date = March 1991 | pmid = 2006187 | pmc = 51262 | doi = 10.1073/pnas.88.6.2510 | bibcode = 1991PNAS...88.2510S | doi-access = free }}</ref> an enzyme that catalyzes the introduction of a double bond at the delta-9 position of steraoyl-ACP to produce oleoyl-ACP. This enzyme is responsible for the conversion of saturated fatty acids to unsaturated fatty acids in the synthesis of vegetable oils. This enzyme is derived from endosymbiosis of the chloroplast. * Cyanobacterial DesA (EC 1.14.19.45),<ref name="PUB00004074">{{cite journal | vauthors = Wada H, Gombos Z, Murata N | title = Enhancement of chilling tolerance of a cyanobacterium by genetic manipulation of fatty acid desaturation | journal = Nature | volume = 347 | issue = 6289 | pages = 200–3 | date = September 1990 | pmid = 2118597 | doi = 10.1038/347200a0 | bibcode = 1990Natur.347..200W | s2cid = 4326551 }}</ref> an enzyme that can introduce a second cis double bond at the delta-12 position of fatty acid bound to membrane glycerolipids. This enzyme is involved in chilling tolerance; the phase transition temperature of lipids of cellular membranes being dependent on the degree of unsaturation of fatty acids of the membrane lipids.

== Mechanism and function == Type 1 desaturases have diiron active sites reminiscent of methane monooxygenase. These enzymes are O2-dependent, consistent with their function as either hydroxylation or oxidative dehydrogenation.<ref>{{cite journal | vauthors = Wallar BJ, Lipscomb JD | title = Dioxygen Activation by Enzymes Containing Binuclear Non-Heme Iron Clusters | journal = Chemical Reviews | volume = 96 | issue = 7 | pages = 2625–2658 | date = November 1996 | pmid = 11848839 | doi = 10.1021/cr9500489 | bibcode = 1996ChRv...96.2625W }}</ref>

All desaturases produce unsaturated fatty acids. Unsaturated fatty acids help maintain structure and function of membranes. Highly unsaturated fatty acids (HUFAs) are incorporated into phospholipids and participate in cell signaling.<ref name="Nakamura 2004">{{cite journal | vauthors = Nakamura MT, Nara TY | title = Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases | journal = Annual Review of Nutrition | volume = 24 | pages = 345–376 | date = 2004 | pmid = 15189125 | doi = 10.1146/annurev.nutr.24.121803.063211 }}</ref> Unsaturated fatty acids and their derived fats increase the fluidity of membranes.<ref>{{cite book | vauthors = Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P | chapter = The Fluidity of a Lipid Bilayer Depends on Its Composition | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK26871/#A1874 | page = 588 | title = Molecular Biology of the Cell | edition = 4th | location = New York | publisher = Garland Science | isbn = 978-0-8153-3218-3 | date = 2002 }}</ref>

==Role in human metabolism== Fatty acid desaturase appear in all organisms: for example, bacteria, fungus, plants, animals and humans.<ref name=":0">{{cite journal | vauthors = Los DA, Murata N | title = Structure and expression of fatty acid desaturases | journal = Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism | volume = 1394 | issue = 1 | pages = 3–15 | date = October 1998 | pmid = 9767077 | doi = 10.1016/S0005-2760(98)00091-5 }}</ref> Four desaturase activities occur in humans: Δ9-desaturase, Δ6-desaturase, Δ5-desaturase, and Δ4-desaturase.{{r|Nakamura 2004}}

* Δ9-desaturase (EC 1.14.19.1), also known as stearoyl-CoA desaturase-1 (''SCD1''), is used to synthesize oleic acid, a monounsaturated, ubiquitous component of all cells in the human body, and the major fatty acid in mammalian adipose triglycerides, and also used for phospholipid and cholesteryl ester synthesis.{{r|Nakamura 2004}} Δ9-desaturase produces oleic acid (C18H34O2; 18:1-n9) by desaturating stearic acid (SA: C18H36O2; 18:0), a saturated fatty acid either synthesized in the body from palmitic acid (PA: C16H32O2; 16:0) or ingested directly. * Δ6 desaturase ( EC 1.14.19.3) is required for the synthesis of highly unsaturated fatty acids such as eicosapentaenoic and docosahexaenoic acids (synthesized from α-linolenic acid); arachidonic acid and adrenic acid (synthesized from linoleic acid). This is a multi-stage process requiring successive actions by elongase and desaturase enzymes. The gene coding for Δ6 desaturase production has been located on human chromosome 11.<ref name=":1" /> The gene responsible is ''FADS2''. * Δ5 desaturase (EC 1.14.19.44) is required for the synthesis of arachidonic acid. The gene responsible is ''FADS1'' on chromosome 11.<ref name=":1" /> * Δ4 desaturase (EC 1.14.19.-) is required for the synthesis of docosahexaenoic acid. The gene responsible is ''FADS2'' on chromosome 11.<ref name=pmid26065859>{{cite journal |last1=Park |first1=HG |last2=Park |first2=WJ |last3=Kothapalli |first3=KS |last4=Brenna |first4=JT |title=The fatty acid desaturase 2 (FADS2) gene product catalyzes Δ4 desaturation to yield n-3 docosahexaenoic acid and n-6 docosapentaenoic acid in human cells. |journal=FASEB Journal |date=September 2015 |volume=29 |issue=9 |pages=3911–9 |doi=10.1096/fj.15-271783 |doi-access=free |pmid=26065859|pmc=4550368 }}</ref>

Synthesis of LC-PUFAs in humans and many other eukaryotes starts with:

* Linoleic acid (LA: C18H32O2; 18:2-n6) → Δ6-desaturation → ''γ''-linolenic acid (GLA: C18H30O2; 18:3-n6) → Δ6-specific elongase (introducing two carbons) → dihomo-gamma-linolenic acid DGLA: C20H34O2; 20:3-n6) → Δ5-desaturase → arachidonic acid (AA: C20H32O2; 20:4-n6) → also endocannabinoids. * α-Linolenic acid (ALA: C18H30O2; 18:3-n3) → Δ6-desaturation → stearidonic acid (SDA: C18H28O2; 18:4-n3) and/or → Δ6-specific elongase → eicosatetraenoic acid (ETA: C20H32O2; 20:4-n3) → Δ5-desaturase → eicosapentaenoic acid (EPA: C20H30O2; 20:5-n3).

Vertebrates are unable to synthesize polyunsaturated fatty acids because they do not have the necessary fatty acid desaturases to "convert oleic acid (18:1''n''-9) into linoleic acid (18:2''n''-6) and α-linolenic acid (18:3''n''-3)".<ref name=":1">{{cite journal | vauthors = Hastings N, Agaba M, Tocher DR, Leaver MJ, Dick JR, Sargent JR, Teale AJ | title = A vertebrate fatty acid desaturase with Delta 5 and Delta 6 activities | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 25 | pages = 14304–14309 | date = December 2001 | pmid = 11724940 | pmc = 64677 | doi = 10.1073/pnas.251516598 | bibcode = 2001PNAS...9814304H | doi-access = free }}</ref> Linoleic acid (LA) and α-linolenic acid (ALA) are essential for human health and development, and should therefore be consumed in the diet. Their absence has been found responsible for the development of a wide range of diseases such as metabolic disorders,<ref>{{cite journal | vauthors = Charytoniuk T, Zywno H, Berk K, Bzdega W, Kolakowski A, Chabowski A, Konstantynowicz-Nowicka K | title = The Endocannabinoid System and Physical Activity-A Robust Duo in the Novel Therapeutic Approach against Metabolic Disorders | journal = International Journal of Molecular Sciences | volume = 23 | issue = 6 | pages = 3083 | date = March 2022 | pmid = 35328503 | pmc = 8948925 | doi = 10.3390/ijms23063083 | doi-access = free }}</ref> cardiovascular disorders, inflammatory processes, viral infections, certain types of cancer and autoimmune disorders.<ref>{{Cite journal | vauthors = Guil-Guerrero JL, Rincón-Cervera MÁ, Venegas-Venegas E |date=2010 |title=Gamma-linolenic and stearidonic acids: Purification and upgrading of C18-PUFA oils |journal=European Journal of Lipid Science and Technology |language=en |volume=112 |issue=10 |pages=1068–1081 |doi=10.1002/ejlt.200900294 |issn=1438-7697}}</ref>

Human fatty acid desaturases include: DEGS1; DEGS2; FADS1; FADS2; FADS3; FADS6; SCD4; SCD5. Not all of these are included in the "canonical" path of fatty acid metabolism above: some of these prefer to work on sphingolipid tails instead of fatty acid-CoA molecules, others are not expressed in the right place to take on a significant part of the work.

=== Endocannabinoid system ===

* Fatty acids with at least 20 carbons (C20) and three double bonds (20:3) bind to CB1 receptors.<ref>{{cite journal | vauthors = Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V | title = Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 11 | pages = 6402–6406 | date = May 2001 | pmid = 11353819 | pmc = 33480 | doi = 10.1073/pnas.101119098 | bibcode = 2001PNAS...98.6402B | doi-access = free }}</ref> * Arachidonic acid (AA) is also the catalyst to the formation of the two main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). **Anandamide (AEA: C22H37NO2; 20:4,n-6) is an ''N''-acylethanolamine resulting from the formal condensation of the carboxyl group of arachidonic acid (AA: C20H32O2; 20:4-n6) with the amino group of ethanolamine (C2H7NO), bind preferably to CB1 receptors.<ref>{{Cite web | work = PubChem |title=Anandamide |url=https://pubchem.ncbi.nlm.nih.gov/compound/5281969 |access-date=2022-11-28 | publisher = U.S. National Library of Medicine |language=en}}</ref> ** 2-Arachidonoylglycerol (2-AG: C23H38O4; 20:4-n6) is an endogenous agonist of the cannabinoid receptors (CB1 and CB2), and the physiological ligand for the cannabinoid CB2 receptor.<ref>{{cite journal | vauthors = Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, Suhara Y, Takayama H, Waku K | display-authors = 6 | title = Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells | language = English | journal = The Journal of Biological Chemistry | volume = 275 | issue = 1 | pages = 605–612 | date = January 2000 | pmid = 10617657 | doi = 10.1074/jbc.275.1.605 | doi-access = free }}</ref> It is an ester formed from omega-6-arachidonic acid (AA: C20H32O2; 20:4-n6) and glycerol (C3H8O3).<ref>{{Cite web | work = PubChem |title=2-Arachidonoylglycerol |url=https://pubchem.ncbi.nlm.nih.gov/compound/5282280 |access-date=2022-11-28 | publisher = U.S. National Library of Medicine |language=en}}</ref>

== In non-human metabolism == The desaturase activities found in non-vertebrate animals, bacteria, and plants provide the essential fatty acids that humans cannot make.<ref name=":2" />

Oleic acid (18:1''n''-9) is converted into linoleic acid (18:2''n''-6) by a Δ12 desaturase, and then into α-linolenic acid (18:3''n''-3) by a Δ15 desaturase.<ref name=":2" />

By a Δ17-desaturase (also not found in humans), gamma-linolenic acid (GLA; 18:3 n-6) can be further converted to stearidonic acid (SDA: C18H28O2; 18:4-n3), dihomo-gamma-linolenic acid (DHGLA/DGLA; 20:3-n6) to eicosatetraenoic acid (ETA; 20:4 n-3; omega-3 arachidonic acid)<ref>{{Cite web | work = PubChem |title=8,11,14,17-Eicosatetraenoic acid |url=https://pubchem.ncbi.nlm.nih.gov/compound/3080584 |access-date=2022-11-27 | publisher = U.S. National Library of Medicine |language=en}}</ref> and arachidonic acid (AA; 20:4 n-6) to eicosapentaenoic acid (EPA; 20:5 n-3), respectively.<ref name=":2" />

=== Industrial relevance===

The ACP desaturases play a critical role in the biosynthesis of unsaturated fatty acids in plants, and are very specific to their substrates.<ref name="PUB12413540">{{cite journal|last=Behrouzian|first=B|author2=Buist, BH|title=Fatty acid desaturation: variations on an oxidative theme|journal=Current Opinion in Chemical Biology|year=2002|volume=6|issue=5|pages=577–82|doi=10.1016/S1367-5931(02)00365-4| pmid = 12413540}}</ref> A common theme in recent research has been to identify uncommon desaturases in various plants and isolate their genetic code.<ref name ="PUB15012248">{{cite journal|last=Shanklin|first=J|author2=Cahoon, E|title=Desaturation and related modifications of fatty acids|journal=Annual Review of Plant Physiology and Plant Molecular Biology|year=1998|volume=49|pages=611–641|doi=10.1146/annurev.arplant.49.1.611|pmid=15012248|url=https://zenodo.org/record/1234923}}</ref><ref name=PUB11027717>{{cite journal|last=Schultz|first=D|author2=Suh, M. |author3=Ohlrogge|title=Stearoyl-Acyl Carrier Protein and Unusual Acyl-Acyl Carrier Protein Desaturase Activities Are Differentially Influenced by Ferredoxin|journal=Plant Physiology|year=2000|volume=124|issue=2|pages=681–692|doi=10.1104/pp.124.2.681|pmid=11027717|pmc=59173|bibcode=2000PlanP.124..681S}}</ref> This can then be inserted into model cells (such as ''Escherichia coli'') and up-regulated through metabolic engineering to skew the composition of oils produced by the model cells.<ref name=PUB8550538>{{cite journal|last=Cahoon|first=E|author2=Mills, L. |author3=Shanklin, J.|title=Modification of the fatty acid composition of Escherichia coli by coexpression of a plant acyl-acyl carrier protein desaturase and ferredoxin|journal=Journal of Bacteriology|year=1996|volume=178|issue=3|pages=936–939|pmid=8550538|pmc=177750|doi=10.1128/jb.178.3.936-939.1996}}</ref>

Manipulation of desaturase genes enable or enhance the production of many economically valuable nutraceutical ingredients, such as: * By copying (mainly CoA) desaturase genes from other organisms into plants, scientists have successfully produced plants that accumulate DHA and EPA in their oils, creating a new source of these nutrients.<ref>{{cite journal | vauthors = Ruiz-Lopez N, Haslam RP, Napier JA, Sayanova O | title = Successful high-level accumulation of fish oil omega-3 long-chain polyunsaturated fatty acids in a transgenic oilseed crop | journal = The Plant Journal | volume = 77 | issue = 2 | pages = 198–208 | date = January 2014 | pmid = 24308505 | pmc = 4253037 | doi = 10.1111/tpj.12378 | bibcode = 2014PlJ....77..198R }}</ref> Some of these oils have received approval for human use while others are approved for animal feed (to increase the nutrition of the meat produced by these animals). This is important because the world does not produce enough of the two fatty acids for consumption by the entire human population at recommended levels.<ref name="pmid33776584">{{cite journal |last1=West |first1=AL |last2=Miles |first2=EA |last3=Lillycrop |first3=KA |last4=Napier |first4=JA |last5=Calder |first5=PC |last6=Burdge |first6=GC |title=Genetically modified plants are an alternative to oily fish for providing n-3 polyunsaturated fatty acids in the human diet: A summary of the findings of a Biotechnology and Biological Sciences Research Council funded project. |journal=Nutrition Bulletin |date=March 2021 |volume=46 |issue=1 |pages=60–68 |doi=10.1111/nbu.12478 |pmid=33776584 |pmc=7986926}}</ref> * Overexpression of a Δ5 desaturase increases EPA production in the diatom ''Phaeodactylum''. This technique can potentially be applied to microalgae, which is currently used to make DHA and EPA.<ref>{{cite journal |last1=He |first1=Wenjin |last2=Chen |first2=Qingying |last3=Ye |first3=Haoying |last4=Gao |first4=Pingru |last5=Wu |first5=Bina |last6=Meng |first6=Wenchu |last7=Zheng |first7=Wenhui |last8=Shi |first8=Jianhua |last9=Murong |first9=Haien |title=Analysis of the Fatty Acid Desaturase Gene Family and Construction and Screening of High-EPA Transgenic Strains in Phaeodactylum tricornutum |journal=Journal of Marine Science and Engineering |date=13 December 2025 |volume=13 |issue=12 |pages=2369 |doi=10.3390/jmse13122369 |doi-access=free |bibcode=2025JMSE...13.2369H }}</ref> * ''Mucor circinelloides'', a model organism used in the industry to produce γ-linolenic acid (GLA), can have a ''D6E(GLELO)'' gene overexpressed to produce dihomo-γ-linolenic acid (DGLA). Further adding a delta-17 desaturase from another organism makes it able to accumulate eicosatetraenoic acid (20:4 n-3).<ref>{{cite journal |last1=Wu |first1=Chen |last2=Yang |first2=Junhuan |last3=Li |first3=Shaoqi |last4=Shi |first4=Wenyue |last5=Xue |first5=Futing |last6=Liu |first6=Qing |last7=Naz |first7=Tahira |last8=Mohamed |first8=Hassan |last9=Song |first9=Yuanda |title=Construction of Eicosatetraenoic Acid Producing Cell Factory by Genetic Engineering of Mucor circinelloides |journal=Fermentation |date=12 July 2023 |volume=9 |issue=7 |pages=653 |doi=10.3390/fermentation9070653 |doi-access=free}}</ref>

==Other desaturating enzymes== The following enzymes also "desaturate" substrates but are not conventionally considered desaturases.

===Acyl-CoA dehydrogenases=== Acyl-CoA dehydrogenases are enzymes that catalyze formation of a double bond between C2 (α) and C3 (β) of the acyl-CoA thioester substrates.<ref name=Thorpe>{{cite journal | vauthors = Thorpe C, Kim JJ | title = Structure and mechanism of action of the acyl-CoA dehydrogenases | journal = FASEB Journal | volume = 9 | issue = 9 | pages = 718–25 | date = June 1995 | pmid = 7601336 | doi = 10.1096/fasebj.9.9.7601336 | doi-access = free | s2cid = 42549744 }}</ref> Flavin adenine dinucleotide (FAD) is a required co-factor.

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== See also == ''N-''acylethanolamine (NAE)

== References == {{reflist|30em}}

Category:Enzymes