Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY8R02L)

• DOT Name: FAD synthase (FLAD1)
• Synonyms: EC 2.7.7.2; FAD pyrophosphorylase; FMN adenylyltransferase; Flavin adenine dinucleotide synthase
• Gene Name: FLAD1
• Related Disease:
  Myopathy with abnormal lipid metabolism
  Atopic dermatitis
  Bipolar disorder
  Coronary atherosclerosis
  Coronary heart disease
  Depression
  Familial Alzheimer disease
  Familial spontaneous pneumothorax
  Fetal akinesia deformation sequence 1
  Heroin dependence
  Hypospadias
  Inborn error of metabolism
  Inflammatory bowel disease
  Major depressive disorder
  Metabolic disorder
  Multiple acyl-CoA dehydrogenase deficiency
  Neoplasm
  Obesity
  Polycystic ovarian syndrome
  Progressive supranuclear palsy
  Asthma
  Cardiovascular disease
  Type-1/2 diabetes
  Prostate cancer
  Prostate carcinoma
  Gastric cancer
  Stomach cancer
• UniProt ID: FAD1_HUMAN
• EC Number: 2.7.7.2
• Pfam ID: PF00994 ; PF01507
• Sequence:
  MGWDLGTRLFQRQEQRSRLSRIWLEKTRVFLEGSTRTPALPHCLFWLLQVPSTQDPLFPG
  YGPQCPVDLAGPPCLRPLFGGLGGYWRALQRGREGRTMTSRASELSPGRSVTAGIIIVGD
  EILKGHTQDTNTFFLCRTLRSLGVQVCRVSVVPDEVATIAAEVTSFSNRFTHVLTAGGIG
  PTHDDVTFEAVAQAFGDELKPHPKLEAATKALGGEGWEKLSLVPSSARLHYGTDPCTGQP
  FRFPLVSVRNVYLFPGIPELLRRVLEGMKGLFQNPAVQFHSKELYVAADEASIAPILAEA
  QAHFGRRLGLGSYPDWGSNYYQVKLTLDSEEEGPLEECLAYLTARLPQGSLVPYMPNAVE
  QASEAVYKLAESGSSLGKKVAGALQTIETSLAQYSLTQLCVGFNGGKDCTALLHLFHAAV
  QRKLPDVPNPLQILYIRSISPFPELEQFLQDTIKRYNLQMLEAEGSMKQALGELQARHPQ
  LEAVLMGTRRTDPYSCSLCPFSPTDPGWPAFMRINPLLDWTYRDIWDFLRQLFVPYCILY
  DRGYTSLGSRENTVRNPALKCLSPGGHPTYRPAYLLENEEEERNSRT
• Function: Catalyzes the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme.
• KEGG Pathway:
  Riboflavin metabolism (hsa00740)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Vitamin B2 (riboflavin) metabolism (R-HSA-196843)
• BioCyc Pathway: MetaCyc:HS08520-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopathy with abnormal lipid metabolism	DISJ3BLB	Definitive	Autosomal recessive	[1]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[2]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[3]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[4]
Depression	DIS3XJ69	Strong	Genetic Variation	[5]
Familial Alzheimer disease	DISE75U4	Strong	Altered Expression	[6]
Familial spontaneous pneumothorax	DISNM7SU	Strong	Biomarker	[7]
Fetal akinesia deformation sequence 1	DISKDI9L	Strong	Genetic Variation	[7]
Heroin dependence	DISQ1H57	Strong	Genetic Variation	[8]
Hypospadias	DIS48CCP	Strong	Genetic Variation	[9]
Inborn error of metabolism	DISO5FAY	Strong	Altered Expression	[6]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[10]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[11]
Multiple acyl-CoA dehydrogenase deficiency	DISEFBN7	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Obesity	DIS47Y1K	Strong	Genetic Variation	[13]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[14]
Progressive supranuclear palsy	DISO5KRQ	Strong	Biomarker	[7]
Asthma	DISW9QNS	moderate	Altered Expression	[15]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[16]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[17]
Prostate cancer	DISF190Y	Disputed	Biomarker	[18]
Prostate carcinoma	DISMJPLE	Disputed	Biomarker	[18]
Gastric cancer	DISXGOUK	Limited	Genetic Variation	[19]
Stomach cancer	DISKIJSX	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of FAD synthase (FLAD1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of FAD synthase (FLAD1).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of FAD synthase (FLAD1).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of FAD synthase (FLAD1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of FAD synthase (FLAD1).	[24]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of FAD synthase (FLAD1).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of FAD synthase (FLAD1).	[26]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of FAD synthase (FLAD1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of FAD synthase (FLAD1).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of FAD synthase (FLAD1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of FAD synthase (FLAD1).	[30]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Single Nucleotide Polymorphisms in the FADS Gene Cluster but not the ELOVL2 Gene are Associated with Serum Polyunsaturated Fatty Acid Composition and Development of Allergy (in a Swedish Birth Cohort).Nutrients. 2015 Dec 3;7(12):10100-15. doi: 10.3390/nu7125521.
• [3] Altered polyunsaturated fatty acid levels in relation to proinflammatory cytokines, fatty acid desaturase genotype, and diet in bipolar disorder.Transl Psychiatry. 2019 Aug 27;9(1):208. doi: 10.1038/s41398-019-0536-0.
• [4] -5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators.Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):218-231. doi: 10.1161/ATVBAHA.117.309660. Epub 2017 Oct 26.
• [5] Erythrocyte polyunsaturated fatty acid composition is associated with depression and FADS genotype in Caucasians.Nutr Neurosci. 2018 Oct;21(8):589-601. doi: 10.1080/1028415X.2017.1327685. Epub 2017 May 29.
• [6] Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency. Am J Hum Genet. 2016 Jun 2;98(6):1130-1145. doi: 10.1016/j.ajhg.2016.04.006.
• [7] Pena-Shokeir phenotype (fetal akinesia deformation sequence) revisited.Birth Defects Res A Clin Mol Teratol. 2009 Aug;85(8):677-94. doi: 10.1002/bdra.20611.
• [8] Genetic polymorphisms of FADS1, FADS2, and FADS3 and fatty acid profiles in subjects received methadone maintenance therapy. Prostaglandins Leukot Essent Fatty Acids. 2018 Sep;136:117-121.
• [9] Post-mortem detection of FLAD1 mutations in 2 Turkish siblings with hypotonia in early infancy.Neuromuscul Disord. 2018 Sep;28(9):787-790. doi: 10.1016/j.nmd.2018.05.009. Epub 2018 May 31.
• [10] Comprehensive genetic study of fatty acids helps explain the role of noncoding inflammatory bowel disease associated SNPs and fatty acid metabolism in disease pathogenesis.Prostaglandins Leukot Essent Fatty Acids. 2018 Mar;130:1-10. doi: 10.1016/j.plefa.2018.02.002. Epub 2018 Feb 19.
• [11] Flavin adenine dinucleotide synthase deficiency due to FLAD1 mutation presenting as multiple acyl-CoA dehydrogenation deficiency-like disease: A case report.Brain Dev. 2019 Aug;41(7):638-642. doi: 10.1016/j.braindev.2019.04.002. Epub 2019 Apr 11.
• [12] Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model.Clin Cancer Res. 2011 May 1;17(9):2934-46. doi: 10.1158/1078-0432.CCR-10-1803. Epub 2011 Jan 17.
• [13] The combined effects of FADS gene variation and dietary fats in obesity-related traits in a population from the far north of Sweden: the GLACIER Study.Int J Obes (Lond). 2019 Apr;43(4):808-820. doi: 10.1038/s41366-018-0112-3. Epub 2018 May 24.
• [14] FADS1-FADS2 gene cluster confers risk to polycystic ovary syndrome.Sci Rep. 2016 Feb 16;6:21195. doi: 10.1038/srep21195.
• [15] Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months.Br J Nutr. 2015 Sep 28;114(6):891-8. doi: 10.1017/S0007114515002561. Epub 2015 Aug 18.
• [16] Diet-gene interactions and PUFA metabolism: a potential contributor to health disparities and human diseases.Nutrients. 2014 May 21;6(5):1993-2022. doi: 10.3390/nu6051993.
• [17] Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome.Br J Nutr. 2012 Feb;107(4):547-55. doi: 10.1017/S0007114511003230. Epub 2011 Jul 4.
• [18] Impact of Genetic and Epigenetic Variations Within the FADS Cluster on the Composition and Metabolism of Polyunsaturated Fatty Acids in Prostate Cancer.Prostate. 2016 Sep;76(13):1182-91. doi: 10.1002/pros.23205. Epub 2016 May 16.
• [19] Dietary n-3 and n-6 polyunsaturated fatty acids, the FADS gene, and the risk of gastric cancer in a Korean population.Sci Rep. 2018 Feb 28;8(1):3823. doi: 10.1038/s41598-018-21960-3.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] 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.
• [22] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [23] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [24] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [25] 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.
• [26] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [27] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [28] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [29] 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.
• [30] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.