Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUJUL9S)

• DOT Name: Flavin-containing monooxygenase 2 (FMO2)
• Synonyms: EC 1.14.13.-; Dimethylaniline oxidase 2; FMO 1B1; Pulmonary flavin-containing monooxygenase 2; FMO 2
• Gene Name: FMO2
• UniProt ID: FMO2_HUMAN
• EC Number: 1.14.13.-
• Pfam ID: PF00743
• Sequence:
  MAKKVAVIGAGVSGLISLKCCVDEGLEPTCFERTEDIGGVWRFKENVEDGRASIYQSVVT
  NTSKEMSCFSDFPMPEDFPNFLHNSKLLEYFRIFAKKFDLLKYIQFQTTVLSVRKCPDFS
  SSGQWKVVTQSNGKEQSAVFDAVMVCSGHHILPHIPLKSFPGMERFKGQYFHSRQYKHPD
  GFEGKRILVIGMGNSGSDIAVELSKNAAQVFISTRHGTWVMSRISEDGYPWDSVFHTRFR
  SMLRNVLPRTAVKWMIEQQMNRWFNHENYGLEPQNKYIMKEPVLNDDVPSRLLCGAIKVK
  STVKELTETSAIFEDGTVEENIDVIIFATGYSFSFPFLEDSLVKVENNMVSLYKYIFPAH
  LDKSTLACIGLIQPLGSIFPTAELQARWVTRVFKGLCSLPSERTMMMDIIKRNEKRIDLF
  GESQSQTLQTNYVDYLDELALEIGAKPDFCSLLFKDPKLAVRLYFGPCNSYQYRLVGPGQ
  WEGARNAIFTQKQRILKPLKTRALKDSSNFSVSFLLKILGLLAVVVAFFCQLQWS
• Function: Catalyzes the oxidative metabolism of numerous xenobiotics, including mainly therapeutic drugs and insecticides that contain a soft nucleophile, most commonly nitrogen and sulfur and participates to their bioactivation. Specifically catalyzes S-oxygenation of sulfur derived compounds such as thioureas-derived compounds, thioetherorganophosphates to their sulfenic acid. In vitro, catalyzes S-oxygenation of the second-line antitubercular drugs thiacetazone (TAZ) and ethionamide (ETA), forming a sulfinic acid and a carbodiimide via a postulated sulfenic acid intermediate. Also catalyzes S-oxygenation of the thioether-containing organophosphate insecticides, phorate and disulfoton.
• Tissue Specificity: Expressed in lung (at protein level). Expressed predominantly in lung, and at a much lesser extent in kidney. Also expressed in fetal lung, but not in liver, kidney and brain.
• KEGG Pathway:
  Taurine and hypotaurine metabolism (hsa00430)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
• Reactome Pathway: FMO oxidises nucleophiles (R-HSA-217271)

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
Docetaxel	DMDI269	Approved	Flavin-containing monooxygenase 2 (FMO2) affects the response to substance of Docetaxel.	[8]

This DOT Affected the Biotransformations of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methimazole	DM25FL8	Approved	Flavin-containing monooxygenase 2 (FMO2) decreases the oxidation of Methimazole.	[9]
Propranolol	DM79NTF	Approved	Flavin-containing monooxygenase 2 (FMO2) increases the oxidation of Propranolol.	[10]
Trifluoperazine	DMKBYWI	Approved	Flavin-containing monooxygenase 2 (FMO2) increases the oxidation of Trifluoperazine.	[10]
PMID28454500-Compound-96	DM2A75P	Patented	Flavin-containing monooxygenase 2 (FMO2) increases the oxidation of PMID28454500-Compound-96.	[10]
Benzydamine	DMEQL9U	Discontinued in Phase 2	Flavin-containing monooxygenase 2 (FMO2) increases the oxidation of Benzydamine.	[10]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Thiourea	DMUELHN	Investigative	Flavin-containing monooxygenase 2 (FMO2) increases the metabolism of Thiourea.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Flavin-containing monooxygenase 2 (FMO2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Flavin-containing monooxygenase 2 (FMO2).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Flavin-containing monooxygenase 2 (FMO2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Flavin-containing monooxygenase 2 (FMO2).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Flavin-containing monooxygenase 2 (FMO2).	[4]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Flavin-containing monooxygenase 2 (FMO2).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Flavin-containing monooxygenase 2 (FMO2).	[7]

References

• [1] 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.
• [2] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [8] Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS. 2013 Jul;17(7):353-67. doi: 10.1089/omi.2013.0019. Epub 2013 Jun 11.
• [9] Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Pharmacogenet Genomics. 2005 Apr;15(4):245-56. doi: 10.1097/01213011-200504000-00008.
• [10] Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis. Microb Cell Fact. 2015 Jun 12;14:82.
• [11] Genetic polymorphisms of flavin-containing monooxygenase (FMO). Drug Metab Rev. 2002 Aug;34(3):523-32. doi: 10.1081/dmr-120005653.