Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9RVXGE)

• DOT Name: Fatty acid desaturase 3 (FADS3)
• Synonyms: FADS3; EC 1.14.19.-; Delta(13) fatty acid desaturase; Delta(13) desaturase
• Gene Name: FADS3
• Related Disease:
  Coronary heart disease
  Bietti crystalline corneoretinal dystrophy
  Hyperlipidemia, familial combined, LPL related
  Amyotrophic lateral sclerosis
  Marfan syndrome
  Non-insulin dependent diabetes
• UniProt ID: FADS3_HUMAN
• EC Number: 1.14.19.-
• Pfam ID: PF00173 ; PF00487
• Sequence:
  MGGVGEPGPREGPAQPGAPLPTFCWEQIRAHDQPGDKWLVIERRVYDISRWAQRHPGGSR
  LIGHHGAEDATDAFRAFHQDLNFVRKFLQPLLIGELAPEEPSQDGPLNAQLVEDFRALHQ
  AAEDMKLFDASPTFFAFLLGHILAMEVLAWLLIYLLGPGWVPSALAAFILAISQAQSWCL
  QHDLGHASIFKKSWWNHVAQKFVMGQLKGFSAHWWNFRHFQHHAKPNIFHKDPDVTVAPV
  FLLGESSVEYGKKKRRYLPYNQQHLYFFLIGPPLLTLVNFEVENLAYMLVCMQWADLLWA
  ASFYARFFLSYLPFYGVPGVLLFFVAVRVLESHWFVWITQMNHIPKEIGHEKHRDWVSSQ
  LAATCNVEPSLFTNWFSGHLNFQIEHHLFPRMPRHNYSRVAPLVKSLCAKHGLSYEVKPF
  LTALVDIVRSLKKSGDIWLDAYLHQ
• Function: Mammals have different sphingoid bases that differ in their length and/or pattern of desaturation and hydroxyl groups. The predominant sphingoid base that comprises mammalian ceramides is sphing-4-enine (sphingosine or SPH) which has a trans (E) desaturation at carbon 4. FADS3 is a desaturase that introduces a cis (Z) double bond between carbon 14 and carbon 15 of the sphingoid base (also known as long chain base, LCB), producing LCBs such as sphinga-4,14-dienine (SPD, d18:2(4E,14Z)) from SPH. Prefers SPH-containing ceramides (N-acylsphing-4-enines) as substrates. Capable of metabolizing also the SPH in its free form. SPD ceramides occur widely in mammalian tissues and cells. Due to their unusual structure containing a cis double bond, SPD ceramides may have an opposite, negative role in lipid microdomain formation relative to conventional ceramides. Could be involved in the detoxification of 1-deoxy sphingolipids, by desaturating the cytotoxic 1-deoxysphinganine (1-deoxySA, m18:0), produced under pathological conditions, to 1-deoxysphingenine (1-deoxysphingosine, 1-deoxySO, m18:1) (Probable). Although prefers SPH-containing ceramides (N-acylsphing-4-enines) as substrates, it also exhibits activity toward dihydrosphingosine-containing CERs (N-acylsphinganines) and produces 14Z-SPH-containing sphingolipids,which can be found in patients with DEGS1 mutations. Its desaturase mechanism involves an electron transfer facilitated by cytochrome b5. FADS3 also acts as a methyl-end fatty acyl coenzyme A (CoA) desaturase that introduces a cis double bond between the preexisting double bond and the terminal methyl group of the fatty acyl chain. Desaturates (11E)-octadecenoate (trans-vaccenoate, the predominant trans fatty acid in human milk) at carbon 13 to generate (11E,13Z)-octadecadienoate (also known as conjugated linoleic acid 11E,13Z-CLA).
• Tissue Specificity: Highly expressed in various organs and tissues including liver, kidney, brain, lung, pancreas, testis, ovary and skeletal muscle (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Genetic Variation	[1]
Bietti crystalline corneoretinal dystrophy	DISLJ355	Strong	Altered Expression	[2]
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Genetic Variation	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[4]
Marfan syndrome	DISVEUWZ	Limited	Biomarker	[5]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[6]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Fatty acid desaturase 3 (FADS3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Fatty acid desaturase 3 (FADS3).	[19]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Fatty acid desaturase 3 (FADS3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fatty acid desaturase 3 (FADS3).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Fatty acid desaturase 3 (FADS3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Fatty acid desaturase 3 (FADS3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Fatty acid desaturase 3 (FADS3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Fatty acid desaturase 3 (FADS3).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Fatty acid desaturase 3 (FADS3).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Fatty acid desaturase 3 (FADS3).	[14]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Fatty acid desaturase 3 (FADS3).	[15]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Fatty acid desaturase 3 (FADS3).	[16]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Fatty acid desaturase 3 (FADS3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Fatty acid desaturase 3 (FADS3).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fatty acid desaturase 3 (FADS3).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Fatty acid desaturase 3 (FADS3).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Fatty acid desaturase 3 (FADS3).	[20]

References

• [1] Association of the FADS gene cluster with coronary artery disease and plasma lipid concentrations in the northern Chinese Han population.Prostaglandins Leukot Essent Fatty Acids. 2017 Feb;117:11-16. doi: 10.1016/j.plefa.2017.01.014. Epub 2017 Jan 26.
• [2] Alterations in serum fatty acid concentrations and desaturase activities in Bietti crystalline dystrophy unaffected by CYP4V2 genotypes.Invest Ophthalmol Vis Sci. 2010 Feb;51(2):1092-7. doi: 10.1167/iovs.09-3665. Epub 2009 Sep 24.
• [3] A systems genetics approach implicates USF1, FADS3, and other causal candidate genes for familial combined hyperlipidemia.PLoS Genet. 2009 Sep;5(9):e1000642. doi: 10.1371/journal.pgen.1000642. Epub 2009 Sep 11.
• [4] Systemic down-regulation of delta-9 desaturase promotes muscle oxidative metabolism and accelerates muscle function recovery following nerve injury.PLoS One. 2013 Jun 13;8(6):e64525. doi: 10.1371/journal.pone.0064525. Print 2013.
• [5] Participation of oleic acid in the formation of the aortic aneurysm in Marfan syndrome patients.Prostaglandins Other Lipid Mediat. 2016 Mar;123:46-55. doi: 10.1016/j.prostaglandins.2016.05.001. Epub 2016 May 6.
• [6] Genetic variants in desaturase gene, erythrocyte fatty acids, and risk for type 2 diabetes in Chinese Hans.Nutrition. 2014 Jul-Aug;30(7-8):897-902. doi: 10.1016/j.nut.2014.01.006. Epub 2014 Jan 30.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [16] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [20] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.