Details of Drug Off-Target (DOT)

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

• DOT Name: Acyl-CoA (FADS1)
• Synonyms: 8-3)-desaturase (EC 1.14.19.44; Delta(5) fatty acid desaturase; D5D; Delta(5) desaturase; Delta-5 desaturase; Fatty acid desaturase 1
• Gene Name: FADS1
• UniProt ID: FADS1_HUMAN
• EC Number: 1.14.19.44
• Pfam ID: PF00173 ; PF00487
• Sequence:
  MAPDPVAAETAAQGPTPRYFTWDEVAQRSGCEERWLVIDRKVYNISEFTRRHPGGSRVIS
  HYAGQDATDPFVAFHINKGLVKKYMNSLLIGELSPEQPSFEPTKNKELTDEFRELRATVE
  RMGLMKANHVFFLLYLLHILLLDGAAWLTLWVFGTSFLPFLLCAVLLSAVQAQAGWLQHD
  FGHLSVFSTSKWNHLLHHFVIGHLKGAPASWWNHMHFQHHAKPNCFRKDPDINMHPFFFA
  LGKILSVELGKQKKKYMPYNHQHKYFFLIGPPALLPLYFQWYIFYFVIQRKKWVDLAWMI
  TFYVRFFLTYVPLLGLKAFLGLFFIVRFLESNWFVWVTQMNHIPMHIDHDRNMDWVSTQL
  QATCNVHKSAFNDWFSGHLNFQIEHHLFPTMPRHNYHKVAPLVQSLCAKHGIEYQSKPLL
  SAFADIIHSLKESGQLWLDAYLHQ
• Function: [Isoform 1]: Acts as a front-end fatty acyl-coenzyme A (CoA) desaturase that introduces a cis double bond at carbon 5 located between a preexisting double bond and the carboxyl end of the fatty acyl chain. Involved in biosynthesis of highly unsaturated fatty acids (HUFA) from the essential polyunsaturated fatty acids (PUFA) linoleic acid (LA) (18:2n-6) and alpha-linolenic acid (ALA) (18:3n-3) precursors. Specifically, desaturates dihomo-gamma-linoleoate (DGLA) (20:3n-6) and eicosatetraenoate (ETA) (20:4n-3) to generate arachidonate (AA) (20:4n-6) and eicosapentaenoate (EPA) (20:5n-3), respectively. As a rate limiting enzyme for DGLA (20:3n-6) and AA (20:4n-6)-derived eicosanoid biosynthesis, controls the metabolism of inflammatory lipids like prostaglandin E2, critical for efficient acute inflammatory response and maintenance of epithelium homeostasis. Contributes to membrane phospholipid biosynthesis by providing AA (20:4n-6) as a major acyl chain esterified into phospholipids. In particular, regulates phosphatidylinositol-4,5-bisphosphate levels, modulating inflammatory cytokine production in T-cells. Also desaturates (11E)-octadecenoate (trans-vaccenoate)(18:1n-9), a metabolite in the biohydrogenation pathway of LA (18:2n-6); [Isoform 2]: Does not exhibit any catalytic activity toward 20:3n-6, but it may enhance FADS2 activity.
• Tissue Specificity: Widely expressed, with highest levels in liver, brain, adrenal gland and heart. Highly expressed in fetal liver and brain.
• KEGG Pathway:
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway:
  Linoleic acid (LA) metabolism (R-HSA-2046105)
  alpha-linolenic acid (ALA) metabolism (R-HSA-2046106)
  PPARA activates gene expression (R-HSA-1989781)
• BioCyc Pathway: MetaCyc:HS07617-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Acyl-CoA (FADS1) affects the response to substance of Fluorouracil.	[24]

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 Acyl-CoA (FADS1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Acyl-CoA (FADS1).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acyl-CoA (FADS1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acyl-CoA (FADS1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acyl-CoA (FADS1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Acyl-CoA (FADS1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Acyl-CoA (FADS1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Acyl-CoA (FADS1).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Acyl-CoA (FADS1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Acyl-CoA (FADS1).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Acyl-CoA (FADS1).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Acyl-CoA (FADS1).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Acyl-CoA (FADS1).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Acyl-CoA (FADS1).	[13]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Acyl-CoA (FADS1).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Acyl-CoA (FADS1).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Acyl-CoA (FADS1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Acyl-CoA (FADS1).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Acyl-CoA (FADS1).	[18]
Ciglitazone	DMAPO0T	Preclinical	Ciglitazone increases the expression of Acyl-CoA (FADS1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Acyl-CoA (FADS1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Acyl-CoA (FADS1).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Acyl-CoA (FADS1).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Acyl-CoA (FADS1).	[21]
geraniol	DMS3CBD	Investigative	geraniol decreases the activity of Acyl-CoA (FADS1).	[22]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Acyl-CoA (FADS1).	[23]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Acyl-CoA (FADS1).	[23]
25-hydroxycholesterol	DMCHAQ7	Investigative	25-hydroxycholesterol decreases the expression of Acyl-CoA (FADS1).	[14]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [10] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [11] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] Delta5 desaturase mRNA levels are increased by simvastatin via SREBP-1 at early stages, not via PPARalpha, in THP-1 cells. Eur J Pharmacol. 2007 Oct 1;571(2-3):97-105.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [18] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [22] Effect of geraniol on fatty-acid and mevalonate metabolism in the human hepatoma cell line Hep G2. Biochem Cell Biol. 2006 Feb;84(1):102-11.
• [23] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.