Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT750IJM)

• DOT Name: DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F)
• Synonyms: EC 3.5.4.38; Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3F; A3F
• Gene Name: APOBEC3F
• Related Disease:
  Hepatitis B virus infection
  HIV infectious disease
  Immunodeficiency
  Hepatocellular carcinoma
  Pneumocystis pneumonia
• UniProt ID: ABC3F_HUMAN
• PDB ID: 3WUS; 4IOU; 4J4J; 5HX4; 5HX5; 5W2M; 5ZVA; 5ZVB; 6NIL
• EC Number: 3.5.4.38
• Pfam ID: PF18782
• Sequence:
  MKPHFRNTVERMYRDTFSYNFYNRPILSRRNTVWLCYEVKTKGPSRPRLDAKIFRGQVYS
  QPEHHAEMCFLSWFCGNQLPAYKCFQITWFVSWTPCPDCVAKLAEFLAEHPNVTLTISAA
  RLYYYWERDYRRALCRLSQAGARVKIMDDEEFAYCWENFVYSEGQPFMPWYKFDDNYAFL
  HRTLKEILRNPMEAMYPHIFYFHFKNLRKAYGRNESWLCFTMEVVKHHSPVSWKRGVFRN
  QVDPETHCHAERCFLSWFCDDILSPNTNYEVTWYTSWSPCPECAGEVAEFLARHSNVNLT
  IFTARLYYFWDTDYQEGLRSLSQEGASVEIMGYKDFKYCWENFVYNDDEPFKPWKGLKYN
  FLFLDSKLQEILE
• Function: DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits antiviral activity against viruse such as HIV-1 or HIV-2. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity also against hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV) and may inhibit the mobility of LTR and non-LTR retrotransposons. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.
• Tissue Specificity: Widely expressed. Highly expressed in ovary.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Human immunodeficiency virus 1 infection (hsa05170)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[1]
HIV infectious disease	DISO97HC	Strong	Biomarker	[2]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[4]
Pneumocystis pneumonia	DISFSOM3	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[11]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA dC->dU-editing enzyme APOBEC-3F (APOBEC3F).	[13]

References

• [1] Hepatitis B: modern concepts in pathogenesis--APOBEC3 cytidine deaminases as effectors in innate immunity against the hepatitis B virus.Curr Opin Infect Dis. 2008 Jun;21(3):298-303. doi: 10.1097/QCO.0b013e3282fe1bb2.
• [2] Stably expressed APOBEC3F has negligible antiviral activity.J Virol. 2010 Nov;84(21):11067-75. doi: 10.1128/JVI.01249-10. Epub 2010 Aug 11.
• [3] Increased APOBEC3G and APOBEC3F expression is associated with low viral load and prolonged survival in simian immunodeficiency virus infected rhesus monkeys.Retrovirology. 2011 Sep 28;8:77. doi: 10.1186/1742-4690-8-77.
• [4] Bufalin inhibits cell proliferation and migration of hepatocellular carcinoma cells via APOBEC3F induced intestinal immune network for IgA production signaling pathway.Biochem Biophys Res Commun. 2018 Sep 10;503(3):2124-2131. doi: 10.1016/j.bbrc.2018.07.169. Epub 2018 Aug 6.
• [5] Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.PLoS Genet. 2016 Mar 4;12(3):e1005921. doi: 10.1371/journal.pgen.1005921. eCollection 2016 Mar.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Estrogen directly activates AID transcription and function. J Exp Med. 2009 Jan 16;206(1):99-111. doi: 10.1084/jem.20080521. Epub 2009 Jan 12.
• [10] 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.
• [11] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.