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Stearoyl-CoA 9-desaturase

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stearoyl-CoA 9-desaturase
Identifiers
EC no.1.14.19.1
CAS no.9014-34-0[permanent dead link‍]
Alt. namesDelta9-desaturase, acyl-CoA desaturase, fatty acid desaturase, and stearoyl-CoA, hydrogen-donor:oxygen oxidoreductase
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
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PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
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In mammals, the SCD-1 reaction requires molecular oxygen, NAD(P)-cytochrome b5 reductase, cytochrome b5 to conduct an electron flow from NADPH to the terminal electron acceptor molecular oxygen, releasing water.

Stearoyl-CoA desaturase (Δ-9-desaturase or SCD-1) is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAs), specifically oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA.[1] Oleate and palmitoleate are major components of membrane phospholipids, cholesterol esters and alkyl-diacylglycerol. In humans, the enzyme is present in two isoforms, encoded respectively by the SCD1 and SCD5 genes.[2][3][4]

Stearoyl-CoA desaturase-1 is a key enzyme in fatty acid metabolism. It is responsible for forming a double bond in stearoyl-CoA. This is how the monounsaturated fatty acid oleic acid is produced from the saturated fatty acid, stearic acid.

A series of redox reactions, during which two electrons flow from NADH to flavoprotein cytochrome b5, then to the electron acceptor cytochrome b5 as well as molecular oxygen introduces a single double bond within a row of methylene fatty acyl-CoA substrates.[5] The complexed enzyme adds a single double bond between the C9 and C10 of long-chain acyl-CoAs from de-novo synthesis.[1]

This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with oxidation of a pair of donors resulting in the reduction of O to two molecules of water. The systematic name of this enzyme class is stearoyl-CoA,ferrocytochrome-b5:oxygen oxidoreductase (9,10-dehydrogenating). This enzyme participates in polyunsaturated fatty acid biosynthesis and PPAR signaling pathway.[citation needed] It employs one cofactor, iron.

Function

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Stearoyl–CoA (black) held in a kinked conformation by SCD1's binding pocket which determines which bond is desaturated. (PDB: 4ZYO​)

Stearoyl-CoA desaturase (SCD; EC 1.14.19.1) is an iron-containing enzyme that catalyzes a rate-limiting step in the synthesis of unsaturated fatty acids. The principal product of SCD is oleic acid, which is formed by desaturation of stearic acid. The ratio of stearic acid to oleic acid has been implicated in the regulation of cell growth and differentiation through effects on cell membrane fluidity and signal transduction.[citation needed]

Four SCD isoforms, Scd1 through Scd4, have been identified in mouse. In contrast, only 2 SCD isoforms, SCD1 and SCD5 (MIM 608370, Uniprot Q86SK9), have been identified in human. SCD1 shares about 85% amino acid identity with all 4 mouse SCD isoforms, as well as with rat Scd1 and Scd2. In contrast, SCD5 (also known as hSCD2) shares limited homology with the rodent SCDs and appears to be unique to primates.[2][6][7][8]

SCD-1 is an important metabolic control point. Inhibition of its expression may enhance the treatment of a host of metabolic diseases.[9] One of the unanswered questions is that SCD remains a highly regulated enzyme, even though oleate is readily available, as it is an abundant monounsaturated fatty acid in dietary fat.

It catalyzes the chemical reaction

stearoyl-CoA + 2 ferrocytochrome b5 + O2 + 2 H+ oleoyl-CoA + 2 ferricytochrome b5 + 2 H2O

The 4 substrates of this enzyme are stearoyl-CoA, ferrocytochrome b5, O2, and H+, whereas its 3 products are oleoyl-CoA, ferricytochrome b5, and H2O.

Structure

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The enzyme's structure is key to its function. SCD-1 consists of four transmembrane domains. Both the amino and carboxyl terminus and eight catalytically important histidine regions, which collectively bind iron within the catalytic center of the enzyme, lie in the cytosol region. The five cysteines in SCD-1 are located within the lumen of the endoplasmic reticulum.[10]

The substrate binding site is long, thin and hydrophobic and kinks the substrate tail at the location where the di-iron catalytic centre introduces the double bond.[11]

SCD is biologically active as a dimer with the major ligand, stearyl-CoA (magenta), docked to the active site.[citation needed] (PDB: 4YMK​)

The literature suggests that the enzyme accomplishes the desaturation reaction by removing the first hydrogen at C9 position and then the second hydrogen from the C-10 position.[12] Because the C-9 and C-10 are positioned close to the iron-containing center of the enzyme, this mechanism is hypothesized to be specific for the position at which the double bond is formed.

Role in human disease

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Monounsaturated fatty acids, the products of SCD-1 catalyzed reactions, can serve as substrates for the synthesis of various kinds of lipids, including phospholipids, triglycerides, and can also be used as mediators in signal transduction and differentiation.[13] Because MUFAs are heavily utilized in cellular processes, variation in SCD activity in mammals is expected to influence physiological variables, including cellular differentiation, insulin sensitivity, metabolic syndrome, atherosclerosis, cancer, and obesity. SCD-1 deficiency results in reduced adiposity, increased insulin sensitivity, and resistance to diet-induced obesity.[14]

Under non-fasting conditions, SCD-1 mRNA is highly expressed in white adipose tissue, brown adipose tissue, and the Harderian gland.[15] SCD-1 expression is significantly increased in liver tissue and heart in response to a high-carbohydrate diet, whereas SCD-2 expression is observed in brain tissue and induced during the neonatal myelination.[16] Diets high in high-saturated as well as monounsaturated-fat can also increase SCD-1 expression, although not to the extent of the lipogenic effect of a high-carb diet.[17]

Elevated expression levels of SCD1 is found to be correlated with obesity [18] and tumor malignancy.[19] It is believed that tumor cells obtain most part of their requirement for fatty acids by de novo synthesis. This phenomenon depends on increased expression of fatty acid biosynthetic enzymes that produce required fatty acids in large quantities.[20] Mice that were fed a high-carbohydrate diet had an induced expression of the liver SCD-1 gene and other lipogenic genes through an insulin-mediated SREBP-1c-dependent mechanism. Activation of SREBP-1c results in upregulated synthesis of MUFAs and liver triglycerides. SCD-1 knockout mice did not increase de novo lipogenesis but created an abundance of cholesterol esters.[21]

SCD1 function has also been shown to be involved in germ cell determination,[22] adipose tissue specification, liver cell differentiation[23] and cardiac development.[24]

The human SCD-1 gene structure and regulation is very similar to that of mouse SCD-1. Overexpression of SCD-1 in humans may be involved in the development of hypertriglyceridemia, atherosclerosis, and diabetes.[25] One study showed that SCD-1 activity was associated with inherited hyperlipidemia. SCD-1 deficiency has also been shown to reduce ceramide synthesis by downregulating serine palmitoyltransferase. This consequently increases the rate of beta-oxidation in skeletal muscle.[26]

In carbohydrate metabolism studies, knockout SCD-1 mice show increased insulin sensitivity. Oleate is a major constituent of membrane phospholipids and membrane fluidity is influenced by the ratio of saturated to monounsaturated fatty acids.[27] One proposed mechanism is that an increase in cell membrane fluidity, consisting largely of lipid, activates the insulin receptor. A decrease in MUFA content of the membrane phospholipids in the SCD-1−/− mice is offset by an increase in polyunsaturated fatty acids, effectively increasing membrane fluidity due to the introduction of more double bonds in the fatty acyl chain.[28]

See also

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References

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  1. ^ a b Paton CM, Ntambi JM (2017-03-08). "Biochemical and physiological function of stearoyl-CoA desaturase". American Journal of Physiology. Endocrinology and Metabolism. 297 (1): E28–E37. doi:10.1152/ajpendo.90897.2008. ISSN 0193-1849. PMC 2711665. PMID 19066317.
  2. ^ a b "Entrez Gene: Stearoyl-CoA desaturase (delta-9-desaturase)". Retrieved 2011-09-29.
  3. ^ "SCD5 stearoyl-CoA desaturase 5 [Homo sapiens (human) ]". Gene. National Library of Medicine. 5 March 2024. Gene ID No. 79966. Retrieved 22 March 2024.
  4. ^ Igal RA, Sinner DI (2021). "Stearoyl-CoA desaturase 5 (SCD5), a Δ-9 fatty acyl desaturase in search of a function". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1866 (1). PMC 8533680. PMID 33049404. Art. No. 158840.
  5. ^ Paton CM, Ntambi JM (2017-03-08). "Biochemical and physiological function of stearoyl-CoA desaturase". American Journal of Physiology. Endocrinology and Metabolism. 297 (1): E28–E37. doi:10.1152/ajpendo.90897.2008. ISSN 0193-1849. PMC 2711665. PMID 19066317.
  6. ^ Zhang L, Ge L, Parimoo S, Stenn K, Prouty SM (May 1999). "Human stearoyl-CoA desaturase: alternative transcripts generated from a single gene by usage of tandem polyadenylation sites". The Biochemical Journal. 340 (Pt 1): 255–64. doi:10.1042/bj3400255. PMC 1220244. PMID 10229681.
  7. ^ Wang J, Yu L, Schmidt RE, Su C, Huang X, Gould K, Cao G (Jul 2005). "Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates". Biochemical and Biophysical Research Communications. 332 (3): 735–42. doi:10.1016/j.bbrc.2005.05.013. PMID 15907797.
  8. ^ Zhang S, Yang Y, Shi Y (2005-05-15). "Characterization of human SCD2, an oligomeric desaturase with improved stability and enzyme activity by cross-linking in intact cells". The Biochemical Journal. 388 (Pt 1): 135–142. doi:10.1042/BJ20041554. ISSN 1470-8728. PMC 1186701. PMID 15610069.
  9. ^ Flowers MT, Ntambi JM (2017-03-09). "Stearoyl-CoA Desaturase and its Relation to High-Carbohydrate Diets and Obesity". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1791 (2): 85–91. doi:10.1016/j.bbalip.2008.12.011. ISSN 0006-3002. PMC 2649790. PMID 19166967.
  10. ^ Bai Y, McCoy JG, Levin EJ, Sobrado P, Rajashankar KR, Fox BG, Zhou M (2015-08-13). "X-ray structure of a mammalian stearoyl-CoA desaturase". Nature. 524 (7564): 252–256. Bibcode:2015Natur.524..252B. doi:10.1038/nature14549. ISSN 0028-0836. PMC 4689147. PMID 26098370.
  11. ^ Wang H, Klein MG, Zou H, Lane W, Snell G, Levin I, Li K, Sang BC (22 June 2015). "Crystal structure of human stearoyl–coenzyme A desaturase in complex with substrate". Nature Structural & Molecular Biology. 22 (7): 581–585. doi:10.1038/nsmb.3049. PMID 26098317. S2CID 205523900.
  12. ^ Nagai J, Bloch K (1965-09-01). "Synthesis of Oleic Acid by Euglena gracilis". Journal of Biological Chemistry. 240 (9): PC3702–PC3703. doi:10.1016/S0021-9258(18)97206-6. ISSN 0021-9258. PMID 5835952.
  13. ^ Miyazaki M, Ntambi JM (2003-02-01). "Role of stearoyl-coenzyme A desaturase in lipid metabolism". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 68 (2): 113–121. doi:10.1016/s0952-3278(02)00261-2. ISSN 0952-3278. PMID 12538075.
  14. ^ Flowers MT, Ntambi JM (2017-03-09). "Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism". Current Opinion in Lipidology. 19 (3): 248–256. doi:10.1097/MOL.0b013e3282f9b54d. ISSN 0957-9672. PMC 4201499. PMID 18460915.
  15. ^ Miyazaki M, Dobrzyn A, Elias PM, Ntambi JM (2005-08-30). "Stearoyl-CoA desaturase-2 gene expression is required for lipid synthesis during early skin and liver development". Proceedings of the National Academy of Sciences of the United States of America. 102 (35): 12501–12506. Bibcode:2005PNAS..10212501M. doi:10.1073/pnas.0503132102. ISSN 0027-8424. PMC 1194914. PMID 16118274.
  16. ^ Miyazaki M, Jacobson MJ, Man WC, Cohen P, Asilmaz E, Friedman JM, Ntambi JM (2003-09-05). "Identification and characterization of murine SCD4, a novel heart-specific stearoyl-CoA desaturase isoform regulated by leptin and dietary factors". The Journal of Biological Chemistry. 278 (36): 33904–33911. doi:10.1074/jbc.M304724200. ISSN 0021-9258. PMID 12815040.
  17. ^ Yue L, Ye F, Gui C, Luo H, Cai J, Shen J, Chen K, Shen X, Jiang H (2017-03-09). "Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation". Protein Science. 14 (3): 812–822. doi:10.1110/ps.04951405. ISSN 0961-8368. PMC 2279270. PMID 15722453.
  18. ^ Hulver MW, Berggren JR, Carper MJ, Miyazaki M, Ntambi JM, Hoffman EP, Thyfault JP, Stevens R, Dohm GL, Houmard JA, Muoio DM (Oct 2005). "Elevated stearoyl-CoA desaturase-1 expression in skeletal muscle contributes to abnormal fatty acid partitioning in obese humans". Cell Metabolism. 2 (4): 251–61. doi:10.1016/j.cmet.2005.09.002. PMC 4285571. PMID 16213227.
  19. ^ Ide Y, Waki M, Hayasaka T, Nishio T, Morita Y, Tanaka H, Sasaki T, Koizumi K, Matsunuma R, Hosokawa Y, Ogura H, Shiiya N, Setou M (2013). "Human breast cancer tissues contain abundant phosphatidylcholine(36:1) with high stearoyl-CoA desaturase-1 expression". PLOS ONE. 8 (4): e61204. Bibcode:2013PLoSO...861204I. doi:10.1371/journal.pone.0061204. PMC 3629004. PMID 23613812.
  20. ^ Mohammadzadeh F, Mosayebi G, Montazeri V, Darabi M, Fayezi S, Shaaker M, Rahmati M, Baradaran B, Mehdizadeh A, Darabi M (Jun 2014). "Fatty Acid Composition of Tissue Cultured Breast Carcinoma and the Effect of Stearoyl-CoA Desaturase 1 Inhibition". Journal of Breast Cancer. 17 (2): 136–42. doi:10.4048/jbc.2014.17.2.136. PMC 4090315. PMID 25013434.
  21. ^ Flowers MT, Groen AK, Oler AT, Keller MP, Choi Y, Schueler KL, Richards OC, Lan H, Miyazaki M (2006-12-01). "Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet". Journal of Lipid Research. 47 (12): 2668–2680. doi:10.1194/jlr.M600203-JLR200. ISSN 0022-2275. PMID 17005996.
  22. ^ Ben-David U, Gan QF, Golan-Lev T, Arora P, Yanuka O, Oren YS, Leikin-Frenkel A, Graf M, Garippa R, Boehringer M, Gromo G, Benvenisty N (Feb 2013). "Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen". Cell Stem Cell. 12 (2): 167–79. doi:10.1016/j.stem.2012.11.015. PMID 23318055.
  23. ^ Rahimi Y, Mehdizadeh A, Nozad Charoudeh H, Nouri M, Valaei K, Fayezi S, Darabi M (Dec 2015). "Hepatocyte differentiation of human induced pluripotent stem cells is modulated by stearoyl-CoA desaturase 1 activity". Development, Growth & Differentiation. 57 (9): 667–74. doi:10.1111/dgd.12255. PMID 26676854.
  24. ^ Zhang L, Pan Y, Qin G, Chen L, Chatterjee TK, Weintraub NL, Tang Y (2014). "Inhibition of stearoyl-coA desaturase selectively eliminates tumorigenic Nanog-positive cells: improving the safety of iPS cell transplantation to myocardium". Cell Cycle. 13 (5): 762–71. doi:10.4161/cc.27677. PMC 3979912. PMID 24394703.
  25. ^ Mar-Heyming R, Miyazaki M, Weissglas-Volkov D, Kolaitis NA, Sadaat N, Plaisier C, Pajukanta P, Cantor RM, de Bruin TW (2008-06-01). "Association of stearoyl-CoA desaturase 1 activity with familial combined hyperlipidemia". Arteriosclerosis, Thrombosis, and Vascular Biology. 28 (6): 1193–1199. doi:10.1161/ATVBAHA.107.160150. ISSN 1524-4636. PMC 2758768. PMID 18340007.
  26. ^ Dobrzyn P, Dobrzyn A (2013-01-01). Ntambi JM (ed.). Stearoyl-CoA Desaturase Genes in Lipid Metabolism. Springer New York. pp. 85–101. doi:10.1007/978-1-4614-7969-7_8. ISBN 9781461479680.
  27. ^ Rahman SM, Dobrzyn A, Dobrzyn P, Lee SH, Miyazaki M, Ntambi JM (2003-09-16). "Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle". Proceedings of the National Academy of Sciences of the United States of America. 100 (19): 11110–11115. Bibcode:2003PNAS..10011110R. doi:10.1073/pnas.1934571100. ISSN 0027-8424. PMC 196935. PMID 12960377.
  28. ^ Hagen RM, Rodriguez-Cuenca S, Vidal-Puig A (2010-06-18). "An allostatic control of membrane lipid composition by SREBP1". FEBS Letters. Gothenburg Special Issue: Molecules of Life. 584 (12): 2689–2698. doi:10.1016/j.febslet.2010.04.004. PMID 20385130. S2CID 10699298.

Bibliography

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Further reading

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