Fatty acid desaturase explained

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.^[1]

Two subgroups of desaturases are recognized:

• 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.^[2]

In the biosynthesis of essential fatty acids, an elongase alternates with various desaturases (for example, Δ6-desaturase) repeatedly inserts an ethyl group, then forms a double bond.

Mechanism and function

Desaturases have diiron active sites reminiscent of methane monooxygenase. These enzymes are O₂-dependent, consistent with their function as either hydroxylation or oxidative dehydrogenation.^[3]

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.^[4]

Unsaturated fatty acids and their derived fats increase the fluidity of membranes.^[5]

Role in human metabolism

Fatty acid desaturase appear in all organisms: for example, bacteria, fungus, plants, animals and humans.^[6] Four desaturases occur in humans: Δ9-desaturase, Δ6-desaturase, Δ5-desaturase, and Δ4-desaturase.

Δ9-desaturase, also known as stearoyl-CoA desaturase-1, 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. 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 and Δ5 desaturases are required for the synthesis of highly unsaturated fatty acids such as eicosopentaenoic 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 genes coding for Δ6 and Δ5 desaturase production have been located on human chromosome 11.

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).

By a Δ17-desaturase, gamma-linolenic acid (GLA: C₁₈H₃₀O₂; 18:3-n6) can be further converted to stearidonic acid (SDA: C₁₈H₂₈O₂; 18:4-n3), dihomo-gamma-linolenic acid (DHGLA/DGLA: C₂₀H₃₄O₂; 20:3-n6) to eicosatetraenoic acid (ETA: C₂₀H₃₂O₂; 20:4-n3; omega-3 arachidonic acid)^[7] and arachidonic acid (AA: C₂₀H₃₂O₂; 20:4-n6) to eicosapentaenoic acid (EPA: C₂₀H₃₀O₂; 20:5-n3), respectively.

• Fatty acids with at least 20 carbons (C₂₀) and three double bonds (20:3) bind to CB1 receptors.^[8]
• 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.^[9]

* 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.^[10] It is an ester formed from omega-6-arachidonic acid (AA: C₂₀H₃₂O₂; 20:4-n6) and glycerol (C₃H₈O₃).^[11]

Vertebrates are unable to synthesize polyunsaturated fatty acids because they do not have the necessary fatty acid desaturases to "convert oleic acid (18:1n-9) into linoleic acid (18:2n-6) and α-linolenic acid (18:3n-3)".^[12] Linoleic acid (LA) and α-linolenic acid (ALA) are essential for human health and development, and should therefore be consumed by diets, like 15 ml of hemp seed oil, or/and 33 gram of hemp seed protein a day,^[13] can provide all the protein, essential fatty acids, and dietary fiber necessary for human survival for one day,^[14] as their absence has been found responsible for the development of a wide range of diseases such as metabolic disorders,^[15] cardiovascular disorders, inflammatory processes, viral infections, certain types of cancer and autoimmune disorders.^[16]

Human fatty acid desaturases include: DEGS1; DEGS2; FADS1; FADS2; FADS3; FADS6; SCD4; SCD5

Classification

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

Family 1 includes Stearoyl-CoA desaturase-1 (SCD) .^[17]

Family 2 is composed of:

• Bacterial fatty acid desaturases.
• Plant stearoyl-acyl-carrier-protein desaturase,^[18] 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.
• Cyanobacterial DesA,^[19] 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.

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.^[20] Flavin adenine dinucleotide (FAD) is a required co-factor.

See also

N-acylethanolamine (NAE)

Notes and References

1. Jiao J, Zhang Y . Transgenic biosynthesis of polyunsaturated fatty acids: a sustainable biochemical engineering approach for making essential fatty acids in plants and animals . Chemical Reviews . 113 . 5 . 3799–3814 . May 2013 . 23421688 . 10.1021/cr300007p .
2. Abedi E, Sahari MA . Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties . Food Science & Nutrition . 2 . 5 . 443–463 . September 2014 . 25473503 . 4237475 . 10.1002/fsn3.121 .
3. Wallar BJ, Lipscomb JD . Dioxygen Activation by Enzymes Containing Binuclear Non-Heme Iron Clusters . Chemical Reviews . 96 . 7 . 2625–2658 . November 1996 . 11848839 . 10.1021/cr9500489 .
4. Nakamura MT, Nara TY . Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases . Annual Review of Nutrition . 24 . 345–376 . 2004 . 15189125 . 10.1146/annurev.nutr.24.121803.063211 .
5. Book: Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P . The Fluidity of a Lipid Bilayer Depends on Its Composition . https://www.ncbi.nlm.nih.gov/books/NBK26871/#A1874 . 588 . Molecular Biology of the Cell . 4th . New York . Garland Science . 978-0-8153-3218-3 . 2002 .
6. Los DA, Murata N . Structure and expression of fatty acid desaturases . Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism . 1394 . 1 . 3–15 . October 1998 . 9767077 . 10.1016/S0005-2760(98)00091-5 .
7. Web site: PubChem . 8,11,14,17-Eicosatetraenoic acid . 2022-11-27 . U.S. National Library of Medicine . en.
8. Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V . Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets . Proceedings of the National Academy of Sciences of the United States of America . 98 . 11 . 6402–6406 . May 2001 . 11353819 . 33480 . 10.1073/pnas.101119098 . 2001PNAS...98.6402B . free .
9. Web site: PubChem . Anandamide . 2022-11-28 . U.S. National Library of Medicine . en.
10. Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, Suhara Y, Takayama H, Waku K . 6 . 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 . English . The Journal of Biological Chemistry . 275 . 1 . 605–612 . January 2000 . 10617657 . 10.1074/jbc.275.1.605 . free .
11. Web site: PubChem . 2-Arachidonoylglycerol . 2022-11-28 . U.S. National Library of Medicine . en.
12. Hastings N, Agaba M, Tocher DR, Leaver MJ, Dick JR, Sargent JR, Teale AJ . A vertebrate fatty acid desaturase with Delta 5 and Delta 6 activities . Proceedings of the National Academy of Sciences of the United States of America . 98 . 25 . 14304–14309 . December 2001 . 11724940 . 64677 . 10.1073/pnas.251516598 . 2001PNAS...9814304H . free .
13. Galasso I, Russo R, Mapelli S, Ponzoni E, Brambilla IM, Battelli G, Reggiani R . Variability in Seed Traits in a Collection of Cannabis sativa L. Genotypes . Frontiers in Plant Science . 7 . 688 . 2016-05-20 . 27242881 . 4873519 . 10.3389/fpls.2016.00688 . free .
14. Web site: Hemp Seed Protein . 2022-11-28 . Innvista . en-US.
15. Charytoniuk T, Zywno H, Berk K, Bzdega W, Kolakowski A, Chabowski A, Konstantynowicz-Nowicka K . The Endocannabinoid System and Physical Activity-A Robust Duo in the Novel Therapeutic Approach against Metabolic Disorders . International Journal of Molecular Sciences . 23 . 6 . 3083 . March 2022 . 35328503 . 8948925 . 10.3390/ijms23063083 . free .
16. Guil-Guerrero JL, Rincón-Cervera MÁ, Venegas-Venegas E . 2010 . Gamma-linolenic and stearidonic acids: Purification and upgrading of C18-PUFA oils . European Journal of Lipid Science and Technology . en . 112 . 10 . 1068–1081 . 10.1002/ejlt.200900294 . 1438-7697.
17. Kaestner KH, Ntambi JM, Kelly Jr TJ, Lane MD . Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA desaturase . The Journal of Biological Chemistry . 264 . 25 . 14755–61 . September 1989 . 10.1016/S0021-9258(18)63763-9 . 2570068 . free .
18. Shanklin J, Somerville C . Stearoyl-acyl-carrier-protein desaturase from higher plants is structurally unrelated to the animal and fungal homologs . Proceedings of the National Academy of Sciences of the United States of America . 88 . 6 . 2510–4 . March 1991 . 2006187 . 51262 . 10.1073/pnas.88.6.2510 . 1991PNAS...88.2510S . free .
19. Wada H, Gombos Z, Murata N . Enhancement of chilling tolerance of a cyanobacterium by genetic manipulation of fatty acid desaturation . Nature . 347 . 6289 . 200–3 . September 1990 . 2118597 . 10.1038/347200a0 . 1990Natur.347..200W . 4326551 .
20. Thorpe C, Kim JJ . Structure and mechanism of action of the acyl-CoA dehydrogenases . FASEB Journal . 9 . 9 . 718–25 . June 1995 . 7601336 . 10.1096/fasebj.9.9.7601336 . free . 42549744 .