Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXML85Y)

• DOT Name: Alpha-ketoglutarate-dependent dioxygenase FTO (FTO)
• Synonyms: Fat mass and obesity-associated protein; U6 small nuclear RNA (2'-O-methyladenosine-N(6)-)-demethylase FTO; EC 1.14.11.-; U6 small nuclear RNA N(6)-methyladenosine-demethylase FTO; EC 1.14.11.-; mRNA (2'-O-methyladenosine-N(6)-)-demethylase FTO; m6A(m)-demethylase FTO; EC 1.14.11.-; mRNA N(6)-methyladenosine demethylase FTO; EC 1.14.11.53; tRNA N1-methyl adenine demethylase FTO; EC 1.14.11.-
• Gene Name: FTO
• Related Disease: Lethal polymalformative syndrome, Boissel type
• UniProt ID: FTO_HUMAN
• PDB ID: 3LFM; 4CXW; 4CXX; 4CXY; 4IDZ; 4IE0; 4IE4; 4IE5; 4IE6; 4IE7; 4QHO; 4QKN; 4ZS2; 4ZS3; 5DAB; 5F8P; 5ZMD; 6AEJ; 6AK4; 6AKW; 7CKK; 7E8Z; 7WCV
• EC Number: 1.14.11.-; 1.14.11.53
• Pfam ID: PF12934 ; PF12933
• Sequence:
  MKRTPTAEEREREAKKLRLLEELEDTWLPYLTPKDDEFYQQWQLKYPKLILREASSVSEE
  LHKEVQEAFLTLHKHGCLFRDLVRIQGKDLLTPVSRILIGNPGCTYKYLNTRLFTVPWPV
  KGSNIKHTEAEIAAACETFLKLNDYLQIETIQALEELAAKEKANEDAVPLCMSADFPRVG
  MGSSYNGQDEVDIKSRAAYNVTLLNFMDPQKMPYLKEEPYFGMGKMAVSWHHDENLVDRS
  AVAVYSYSCEGPEEESEDDSHLEGRDPDIWHVGFKISWDIETPGLAIPLHQGDCYFMLDD
  LNATHQHCVLAGSQPRFSSTHRVAECSTGTLDYILQRCQLALQNVCDDVDNDDVSLKSFE
  PAVLKQGEEIHNEVEFEWLRQFWFQGNRYRKCTDWWCQPMAQLEALWKKMEGVTNAVLHE
  VKREGLPVEQRNEILTAILASLTARQNLRREWHARCQSRIARTLPADQKPECRPYWEKDD
  ASMPLPFDLTDIVSELRGQLLEAKP
• Function: RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis. Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. M6A demethylation by FTO affects mRNA expression and stability. Also able to demethylate m6A in U6 small nuclear RNA (snRNA). Mediates demethylation of N(6),2'-O-dimethyladenosine cap (m6A(m)), by demethylating the N(6)-methyladenosine at the second transcribed position of mRNAs and U6 snRNA. Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping. Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. Also able to repair alkylated DNA and RNA by oxidative demethylation: demethylates single-stranded RNA containing 3-methyluracil, single-stranded DNA containing 3-methylthymine and has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine. Ability to repair alkylated DNA and RNA is however unsure in vivo. Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation. Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells. Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs. Plays an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression.
• Tissue Specificity: Ubiquitously expressed, with relatively high expression in adrenal glands and brain; especially in hypothalamus and pituitary . Highly expressed in highly expressed in acute myeloid leukemias (AML) with t(11;11)(q23;23) with KMT2A/MLL1 rearrangements, t(15;17)(q21;q21)/PML-RARA, FLT3-ITD, and/or NPM1 mutations .
• Reactome Pathway: Reversal of alkylation damage by DNA dioxygenases (R-HSA-73943)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lethal polymalformative syndrome, Boissel type	DISVI1YP	Strong	Autosomal recessive	[1]

3 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 Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[2]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[12]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Alpha-ketoglutarate-dependent dioxygenase FTO (FTO).	[9]

References

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• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [5] 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.
• [6] m6A demethylation of cytidine deaminase APOBEC3B mRNA orchestrates arsenic-induced mutagenesis. J Biol Chem. 2022 Feb;298(2):101563. doi: 10.1016/j.jbc.2022.101563. Epub 2022 Jan 6.
• [7] 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.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [9] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [10] 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.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.