Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT57XWXO)

• DOT Name: Ferroptosis suppressor protein 1 (AIFM2)
• Synonyms: FSP1; EC 1.6.5.-; Apoptosis-inducing factor homologous mitochondrion-associated inducer of death; AMID; p53-responsive gene 3 protein
• Gene Name: AIFM2
• Related Disease:
  Lymphoblastic lymphoma
  Rheumatoid arthritis
  Advanced cancer
• UniProt ID: FSP1_HUMAN
• EC Number: 1.6.5.-
• Pfam ID: PF07992
• Sequence:
  MGSQVSVESGALHVVIVGGGFGGIAAASQLQALNVPFMLVDMKDSFHHNVAALRASVETG
  FAKKTFISYSVTFKDNFRQGLVVGIDLKNQMVLLQGGEALPFSHLILATGSTGPFPGKFN
  EVSSQQAAIQAYEDMVRQVQRSRFIVVVGGGSAGVEMAAEIKTEYPEKEVTLIHSQVALA
  DKELLPSVRQEVKEILLRKGVQLLLSERVSNLEELPLNEYREYIKVQTDKGTEVATNLVI
  LCTGIKINSSAYRKAFESRLASSGALRVNEHLQVEGHSNVYAIGDCADVRTPKMAYLAGL
  HANIAVANIVNSVKQRPLQAYKPGALTFLLSMGRNDGVGQISGFYVGRLMVRLTKSRDLF
  VSTSWKTMRQSPP
• Function: A NAD(P)H-dependent oxidoreductase that acts as a key inhibitor of ferroptosis. At the plasma membrane, catalyzes reduction of coenzyme Q/ubiquinone-10 to ubiquinol-10, a lipophilic radical-trapping antioxidant that prevents lipid oxidative damage and consequently ferroptosis. Acts in parallel to GPX4 to suppress phospholipid peroxidation and ferroptosis. This anti-ferroptotic function is independent of cellular glutathione levels. Also acts as a potent radical-trapping antioxidant by mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle: catalyzes NAD(P)H-dependent reduction of vitamin K (phylloquinone, menaquinone-4 and menadione) to hydroquinone forms. Hydroquinones act as potent radical-trapping antioxidants inhibitor of phospholipid peroxidation and ferroptosis. May play a role in mitochondrial stress signaling. Upon oxidative stress, associates with the lipid peroxidation end product 4-hydroxy-2-nonenal (HNE) forming a lipid adduct devoid of oxidoreductase activity, which then translocates from mitochondria into the nucleus triggering DNA damage and cell death. Capable of DNA binding in a non-sequence specific way.
• Tissue Specificity: Detected in most normal tissues as two transcripts of 1.8 and 4.0 kb in length, respectively. Highly expressed in heart, moderately in liver and skeletal muscles, and expressed at low levels in placenta, lung, kidney, and pancreas. Both transcripts expressed following p53/TP53 induction. The shorter 1.8 kb transcript seems to be the major transcript in EB1 colon cancer cells.
• KEGG Pathway: p53 sig.ling pathway (hsa04115)
• Reactome Pathway: TP53 Regulates Transcription of Genes Involved in Cytochrome C Release (R-HSA-6803204)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lymphoblastic lymphoma	DISB9ZYC	Strong	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]

17 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 Ferroptosis suppressor protein 1 (AIFM2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ferroptosis suppressor protein 1 (AIFM2).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[11]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of Ferroptosis suppressor protein 1 (AIFM2).	[7]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[13]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[18]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal increases the expression of Ferroptosis suppressor protein 1 (AIFM2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Ferroptosis suppressor protein 1 (AIFM2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ferroptosis suppressor protein 1 (AIFM2).	[15]

References

• [1] The inhibitory effect of MEG3/miR-214/AIFM2 axis on the growth of T-cell lymphoblastic lymphoma.Int J Oncol. 2017 Jul;51(1):316-326. doi: 10.3892/ijo.2017.4006. Epub 2017 May 17.
• [2] Studying the effects of haplotype partitioning methods on the RA-associated genomic results from the North American Rheumatoid Arthritis Consortium (NARAC) dataset.J Adv Res. 2019 Jan 18;18:113-126. doi: 10.1016/j.jare.2019.01.006. eCollection 2019 Jul.
• [3] Searching for cancer vulnerabilities amid genetic chaos.Genome Biol. 2017 Aug 3;18(1):147. doi: 10.1186/s13059-017-1283-2.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] 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.
• [12] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [13] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [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] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [19] Methylglyoxal disturbs the expression of antioxidant, apoptotic and glycation responsive genes and triggers programmed cell death in human leukocytes. Toxicol In Vitro. 2019 Mar;55:33-42.