Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT410VP5)

• DOT Name: DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G)
• Synonyms: EC 3.5.4.38; APOBEC-related cytidine deaminase; APOBEC-related protein; ARCD; APOBEC-related protein 9; ARP-9; CEM-15; CEM15; Deoxycytidine deaminase; A3G
• Gene Name: APOBEC3G
• UniProt ID: ABC3G_HUMAN
• PDB ID: 2JYW; 2KBO; 2KEM; 3E1U; 3IQS; 3IR2; 3V4J; 3V4K; 4ROV; 4ROW; 5ZVA; 5ZVB; 6BUX; 6BWY; 6K3J; 6K3K; 7UXD; 8CX0; 8CX1; 8CX2; 8H0I; 8J62
• EC Number: 3.5.4.38
• Pfam ID: PF18782
• Sequence:
  MKPHFRNTVERMYRDTFSYNFYNRPILSRRNTVWLCYEVKTKGPSRPPLDAKIFRGQVYS
  ELKYHPEMRFFHWFSKWRKLHRDQEYEVTWYISWSPCTKCTRDMATFLAEDPKVTLTIFV
  ARLYYFWDPDYQEALRSLCQKRDGPRATMKIMNYDEFQHCWSKFVYSQRELFEPWNNLPK
  YYILLHIMLGEILRHSMDPPTFTFNFNNEPWVRGRHETYLCYEVERMHNDTWVLLNQRRG
  FLCNQAPHKHGFLEGRHAELCFLDVIPFWKLDLDQDYRVTCFTSWSPCFSCAQEMAKFIS
  KNKHVSLCIFTARIYDDQGRCQEGLRTLAEAGAKISIMTYSEFKHCWDTFVDHQGCPFQP
  WDGLDEHSQDLSGRLRAILQNQEN
• Function: DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits potent antiviral activity against Vif-deficient HIV-1. 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 simian immunodeficiency viruses (SIVs), hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV). May inhibit the mobility of LTR and non-LTR retrotransposons.
• Tissue Specificity: Expressed in spleen, testes, ovary and peripheral blood leukocytes and CD4+ lymphocytes. Also expressed in non-permissive peripheral blood mononuclear cells, and several tumor cell lines; no expression detected in permissive lymphoid and non-lymphoid cell lines. Exists only in the LMM form in peripheral blood-derived resting CD4 T-cells and monocytes, both of which are refractory to HIV-1 infection. LMM is converted to a HMM complex when resting CD4 T-cells are activated or when monocytes are induced to differentiate into macrophages. This change correlates with increased susceptibility of these cells to HIV-1 infection.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  APOBEC3G mediated resistance to HIV-1 infection (R-HSA-180689)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[13]

12 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 DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[8]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[9]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G).	[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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] 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.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] 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.
• [9] 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.
• [10] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [11] 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.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.