Stearoyl-CoA desaturase-1

Stearoyl-CoA desaturase (Δ-9-desaturase)

Stearoyl-CoA desaturase-1 bound to its substrate, Stearoyl-CoA (black). The catalytic centre iron ions (red) and water (blue) desaturate a bond in the tail of the substrate, which is held in a kinked conformation by the binding pocket. The enzyme is embedded in the membrane of the endoplasmic reticulum by four transmembrane helices. (PDB: 4ZYO​)
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SCD ; FADS5; MSTP008; SCD1; SCDOS
External IDs OMIM: 604031 HomoloGene: 74538 ChEMBL: 5555 GeneCards: SCD Gene
EC number 1.14.19.1
Orthologs
Species Human Mouse
Entrez 6319 20249
Ensembl ENSG00000099194 ENSMUSG00000037071
UniProt O00767 P13516
RefSeq (mRNA) NM_005063 NM_009127
RefSeq (protein) NP_005054 NP_033153
Location (UCSC) Chr 10:
100.35 – 100.36 Mb		 Chr 19:
44.39 – 44.41 Mb
PubMed search

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. 1 2 "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.
  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

  • Mziaut H, Korza G, Ozols J (Aug 2000). "The N terminus of microsomal Δ 9 stearoyl-CoA desaturase contains the sequence determinant for its rapid degradation". Proceedings of the National Academy of Sciences of the United States of America 97 (16): 8883–8. doi:10.1073/pnas.97.16.8883. PMC: 16790. PMID 10922050. 
  • Samuel W, Kutty RK, Nagineni S, Gordon JS, Prouty SM, Chandraratna RA, Wiggert B (Aug 2001). "Regulation of stearoyl coenzyme A desaturase expression in human retinal pigment epithelial cells by retinoic acid". The Journal of Biological Chemistry 276 (31): 28744–50. doi:10.1074/jbc.M103587200. PMID 11397803. 
  • Zhang L, Ge L, Tran T, Stenn K, Prouty SM (Jul 2001). "Isolation and characterization of the human stearoyl-CoA desaturase gene promoter: requirement of a conserved CCAAT cis-element". The Biochemical Journal 357 (Pt 1): 183–93. doi:10.1042/0264-6021:3570183. PMC: 1221940. PMID 11415448. 
  • Samuel W, Nagineni CN, Kutty RK, Parks WT, Gordon JS, Prouty SM, Hooks JJ, Wiggert B (Jan 2002). "Transforming growth factor-beta regulates stearoyl coenzyme A desaturase expression through a Smad signaling pathway". The Journal of Biological Chemistry 277 (1): 59–66. doi:10.1074/jbc.M108730200. PMID 11677241. 
  • Choi Y, Park Y, Storkson JM, Pariza MW, Ntambi JM (Jun 2002). "Inhibition of stearoyl-CoA desaturase activity by the cis-9,trans-11 isomer and the trans-10,cis-12 isomer of conjugated linoleic acid in MDA-MB-231 and MCF-7 human breast cancer cells". Biochemical and Biophysical Research Communications 294 (4): 785–90. doi:10.1016/S0006-291X(02)00554-5. PMID 12061775. 
  • Attie AD, Krauss RM, Gray-Keller MP, Brownlie A, Miyazaki M, Kastelein JJ, Lusis AJ, Stalenhoef AF, Stoehr JP, Hayden MR, Ntambi JM (Nov 2002). "Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia". Journal of Lipid Research 43 (11): 1899–907. doi:10.1194/jlr.M200189-JLR200. PMID 12401889. 
  • Cohen P, Ntambi JM, Friedman JM (Dec 2003). "Stearoyl-CoA desaturase-1 and the metabolic syndrome". Current Drug Targets. Immune, Endocrine and Metabolic Disorders 3 (4): 271–80. doi:10.2174/1568008033340117. PMID 14683458. 
  • Shiwaku K, Hashimoto M, Kitajima K, Nogi A, Anuurad E, Enkhmaa B, Kim JM, Kim IS, Lee SK, Oyunsuren T, Shido O, Yamane Y (May 2004). "Triglyceride levels are ethnic-specifically associated with an index of stearoyl-CoA desaturase activity and n-3 PUFA levels in Asians". Journal of Lipid Research 45 (5): 914–22. doi:10.1194/jlr.M300483-JLR200. PMID 14967817. 
  • Wang Y, Kurdi-Haidar B, Oram JF (May 2004). "LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1". Journal of Lipid Research 45 (5): 972–80. doi:10.1194/jlr.M400011-JLR200. PMID 14967823. 
  • Rahman SM, Dobrzyn A, Dobrzyn P, Lee SH, Miyazaki M, Ntambi JM (Sep 2003). "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): 11110–5. doi:10.1073/pnas.1934571100. PMC: 196935. PMID 12960377. 

External links


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