Fatty acid desaturase

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 linolenic acid, which is the precursor to alpha-linolenic acid, gamma-linolenic acid, and eicosatrienoic acid.[1]

Fatty acid desaturase, type 1
Identifiers
SymbolFatty_acid_desaturase-1
PfamPF00487
InterProIPR005804
OPM superfamily431
OPM protein4zyo
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Fatty acid desaturase, type 2
Identifiers
SymbolFatty_acid_desaturase-2
PfamPF03405
InterProIPR005067
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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.[4]

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.[4] 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.[7]

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)[8] and arachidonic acid (AA: C20H32O2; 20:4-n6) to eicosapentaenoic acid (EPA: C20H30O2; 20:5-n3), respectively.[2]

  • Fatty acids with at least 20 carbons (C20) and three double bonds (20:3) bind to CB1 receptors.[9]
  • 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.[10]

* 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.[11] It is an ester formed from omega-6-arachidonic acid (AA: C20H32O2; 20:4-n6) and glycerol (C3H8O3).[12]

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)".[7] 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) (EC 1.14.19.1).[17]

Family 2 is composed of:

  • Bacterial fatty acid desaturases.
  • Plant stearoyl-acyl-carrier-protein desaturase (EC 1.14.19.1),[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)

References
  1. Jiao J, Zhang Y (May 2013). "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. doi:10.1021/cr300007p. PMID 23421688.
  2. Abedi E, Sahari MA (September 2014). "Long-chain polyunsaturated fatty acid sources and evaluation of their nutritional and functional properties". Food Science & Nutrition. 2 (5): 443–463. doi:10.1002/fsn3.121. PMC 4237475. PMID 25473503.
  3. Wallar BJ, Lipscomb JD (November 1996). "Dioxygen Activation by Enzymes Containing Binuclear Non-Heme Iron Clusters". Chemical Reviews. 96 (7): 2625–2658. doi:10.1021/cr9500489. PMID 11848839.
  4. Nakamura MT, Nara TY (2004). "Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases". Annual Review of Nutrition. 24: 345–376. doi:10.1146/annurev.nutr.24.121803.063211. PMID 15189125.
  5. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). "The Fluidity of a Lipid Bilayer Depends on Its Composition". Molecular Biology of the Cell (4th ed.). New York: Garland Science. p. 588. ISBN 978-0-8153-3218-3.
  6. Los DA, Murata N (October 1998). "Structure and expression of fatty acid desaturases". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1394 (1): 3–15. doi:10.1016/S0005-2760(98)00091-5. PMID 9767077.
  7. Hastings N, Agaba M, Tocher DR, Leaver MJ, Dick JR, Sargent JR, Teale AJ (December 2001). "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. Bibcode:2001PNAS...9814304H. doi:10.1073/pnas.251516598. PMC 64677. PMID 11724940.
  8. "8,11,14,17-Eicosatetraenoic acid". PubChem. U.S. National Library of Medicine. Retrieved 2022-11-27.
  9. Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V (May 2001). "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. Bibcode:2001PNAS...98.6402B. doi:10.1073/pnas.101119098. PMC 33480. PMID 11353819.
  10. "Anandamide". PubChem. U.S. National Library of Medicine. Retrieved 2022-11-28.
  11. Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, et al. (January 2000). "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". The Journal of Biological Chemistry. 275 (1): 605–612. doi:10.1074/jbc.275.1.605. PMID 10617657.
  12. "2-Arachidonoylglycerol". PubChem. U.S. National Library of Medicine. Retrieved 2022-11-28.
  13. Galasso I, Russo R, Mapelli S, Ponzoni E, Brambilla IM, Battelli G, Reggiani R (2016-05-20). "Variability in Seed Traits in a Collection of Cannabis sativa L. Genotypes". Frontiers in Plant Science. 7: 688. doi:10.3389/fpls.2016.00688. PMC 4873519. PMID 27242881.
  14. "Hemp Seed Protein". Innvista. Retrieved 2022-11-28.
  15. Charytoniuk T, Zywno H, Berk K, Bzdega W, Kolakowski A, Chabowski A, Konstantynowicz-Nowicka K (March 2022). "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. doi:10.3390/ijms23063083. PMC 8948925. PMID 35328503.
  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. 112 (10): 1068–1081. doi:10.1002/ejlt.200900294. ISSN 1438-7697.
  17. Kaestner KH, Ntambi JM, Kelly Jr TJ, Lane MD (September 1989). "Differentiation-induced gene expression in 3T3-L1 preadipocytes. A second differentially expressed gene encoding stearoyl-CoA desaturase" (PDF). The Journal of Biological Chemistry. 264 (25): 14755–61. doi:10.1016/S0021-9258(18)63763-9. PMID 2570068.
  18. Shanklin J, Somerville C (March 1991). "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. Bibcode:1991PNAS...88.2510S. doi:10.1073/pnas.88.6.2510. PMC 51262. PMID 2006187.
  19. Wada H, Gombos Z, Murata N (September 1990). "Enhancement of chilling tolerance of a cyanobacterium by genetic manipulation of fatty acid desaturation". Nature. 347 (6289): 200–3. Bibcode:1990Natur.347..200W. doi:10.1038/347200a0. PMID 2118597. S2CID 4326551.
  20. Thorpe C, Kim JJ (June 1995). "Structure and mechanism of action of the acyl-CoA dehydrogenases". FASEB Journal. 9 (9): 718–25. doi:10.1096/fasebj.9.9.7601336. PMID 7601336. S2CID 42549744.
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