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Stearoyl-CoA desaturase-1

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Template:PBB Stearoyl-CoA desaturase (Δ-9-desaturase) is a protein that in humans is encoded by the SCD gene.[1]

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.

Function

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.

Four SCD isoforms, Scd1 through Scd4, have been identified in mouse. In contrast, only 2 SCD isoforms, SCD1 and SCD5 (MIM 608370), 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 shares limited homology with the rodent SCDs and appears to be unique to primates.[1][2][3]

Structure

The enzyme's structure is key to its function. 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.[4] The enzyme is embedded in the membrane of the endoplasmic reticulum by four transmembrane helices, which hold its active site on the cytoplasmic side.

Role in human disease

Elevated expression levels of SCD1 is found to be correlated with obesity [5] and tumor malignancy.[6] 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.[7]

SCD1 function has also been shown to be involved in germ cell determination,[8] adipose tissue specification, liver cell differentiation[9] and cardiac development.[10]

References

  1. ^ a b "Entrez Gene: Stearoyl-CoA desaturase (delta-9-desaturase)". Retrieved 2011-09-29.
  2. ^ 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) (Pt 1): 255–64. PMC 1220244. PMID 10229681.
  3. ^ 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.
  4. ^ Wang, Hui; Klein, Michael G; Zou, Hua; Lane, Weston; Snell, Gyorgy; Levin, Irena; Li, Ke; Sang, Bi-Ching (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.
  5. ^ 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. PMID 16213227.
  6. ^ 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. doi:10.1371/journal.pone.0061204. PMC 3629004. PMID 23613812.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ 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.
  8. ^ 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.
  9. ^ 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. doi:10.1111/dgd.12255. PMID 26676854.
  10. ^ 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. PMID 24394703.

Further reading


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