Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXIH4X4)

• DOT Name: DNA dC->dU-editing enzyme APOBEC-3H (APOBEC3H)
• Synonyms: EC 3.5.4.38; APOBEC-related protein 10; ARP-10; Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3H; A3H
• Gene Name: APOBEC3H
• Related Disease:
  Hepatocellular carcinoma
  Advanced cancer
  Hepatitis B virus infection
  Immunodeficiency
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: ABC3H_HUMAN
• PDB ID: 5W45; 6B0B; 6BBO; 8FVI
• EC Number: 3.5.4.38
• Pfam ID: PF18771
• Sequence:
  MALLTAETFRLQFNNKRRLRRPYYPRKALLCYQLTPQNGSTPTRGYFENKKKCHAEICFI
  NEIKSMGLDETQCYQVTCYLTWSPCSSCAWELVDFIKAHDHLNLGIFASRLYYHWCKPQQ
  KGLRLLCGSQVPVEVMGFPEFADCWENFVDHEKPLSFNPYKMLEELDKNSRAIKRRLERI
  KIPGVRAQGRYMDILCDAEV
• Function: DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. The A3H-var/haplotype 2 exhibits 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 T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons.
• Tissue Specificity: Expressed in lymphoid organs. Also detected in non-lymphoid tissues including lung, testis, ovary, fetal liver and skin.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Formation of the Editosome (R-HSA-75094)
  mRNA Editing (R-HSA-72200)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[3]
Immunodeficiency	DIS093I0	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[5]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[6]

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-3H (APOBEC3H).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA dC->dU-editing enzyme APOBEC-3H (APOBEC3H).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA dC->dU-editing enzyme APOBEC-3H (APOBEC3H).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA dC->dU-editing enzyme APOBEC-3H (APOBEC3H).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA dC->dU-editing enzyme APOBEC-3H (APOBEC3H).	[9]

References

• [1] Associations between the single nucleotide polymorphisms of APOBEC3A, APOBEC3B and APOBEC3H, and chronic hepatitis B progression and hepatocellular carcinoma in a Chinese population.Mol Med Rep. 2019 Sep;20(3):2177-2188. doi: 10.3892/mmr.2019.10455. Epub 2019 Jul 2.
• [2] The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism.Mol Cell. 2018 Jan 4;69(1):75-86.e9. doi: 10.1016/j.molcel.2017.12.010. Epub 2017 Dec 28.
• [3] Different antiviral activities of natural APOBEC3C, APOBEC3G, and APOBEC3H variants against hepatitis B virus.Biochem Biophys Res Commun. 2019 Oct 8;518(1):26-31. doi: 10.1016/j.bbrc.2019.08.003. Epub 2019 Aug 7.
• [4] Structural basis of chimpanzee APOBEC3H dimerization stabilized by double-stranded RNA.Nucleic Acids Res. 2018 Nov 2;46(19):10368-10379. doi: 10.1093/nar/gky676.
• [5] The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis.Nat Commun. 2016 Sep 21;7:12918. doi: 10.1038/ncomms12918.
• [6] The eQTL-missense polymorphisms of APOBEC3H are associated with lung cancer risk in a Han Chinese population.Sci Rep. 2015 Oct 13;5:14969. doi: 10.1038/srep14969.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.