Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY8QX2R)

• DOT Name: C->U-editing enzyme APOBEC-1 (APOBEC1)
• Synonyms: EC 3.5.4.-; Apolipoprotein B mRNA-editing enzyme catalytic subunit 1; APO1; APOBEC-1; Apolipoprotein B mRNA-editing enzyme 1; EC 3.5.4.36; HEPR; mRNA(cytosine(6666)) deaminase 1
• Gene Name: APOBEC1
• Related Disease:
  Adenocarcinoma
  Barrett esophagus
  Cerebral infarction
  Epilepsy
  Esophageal adenocarcinoma
  Acute myocardial infarction
  Arteriosclerosis
  Atherosclerosis
  Cholelithiasis
  Colon cancer
  Colon carcinoma
  Digestive system neoplasm
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Liver and intrahepatic bile duct neoplasm
  Neoplasm
  Neurofibromatosis type 1
  Testicular germ cell tumor
  Adenoma
  Advanced cancer
  Colorectal carcinoma
  Hyperlipidemia
  Hyperlipoproteinemia
  Intestinal neoplasm
  Obesity
  Temporal lobe epilepsy
• UniProt ID: ABEC1_HUMAN
• PDB ID: 6X91
• EC Number: 3.5.4.-; 3.5.4.36
• Pfam ID: PF18774
• Sequence:
  MTSEKGPSTGDPTLRRRIEPWEFDVFYDPRELRKEACLLYEIKWGMSRKIWRSSGKNTTN
  HVEVNFIKKFTSERDFHPSMSCSITWFLSWSPCWECSQAIREFLSRHPGVTLVIYVARLF
  WHMDQQNRQGLRDLVNSGVTIQIMRASEYYHCWRNFVNYPPGDEAHWPQYPPLWMMLYAL
  ELHCIILSLPPCLKISRRWQNHLTFFRLHLQNCHYQTIPPHILLATGLIHPSVAWR
• Function: Cytidine deaminase catalyzing the cytidine to uridine postranscriptional editing of a variety of mRNAs. Form complexes with cofactors that confer differential editing activity and selectivity. Responsible for the postranscriptional editing of a CAA codon for Gln to a UAA codon for stop in the apolipoprotein B mRNA. Also involved in CGA (Arg) to UGA (Stop) editing in the NF1 mRNA. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation.
• Tissue Specificity: Expressed exclusively in the small intestine.
• Reactome Pathway:
  Formation of the Editosome (R-HSA-75094)
  mRNA Editing (R-HSA-72200)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Barrett esophagus	DIS416Y7	Definitive	Altered Expression	[1]
Cerebral infarction	DISR1WNP	Definitive	Altered Expression	[2]
Epilepsy	DISBB28L	Definitive	Biomarker	[3]
Esophageal adenocarcinoma	DISODWFP	Definitive	Altered Expression	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Cholelithiasis	DISERLZB	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Digestive system neoplasm	DISPOJCT	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[9]
leukaemia	DISS7D1V	Strong	Biomarker	[10]
Leukemia	DISNAKFL	Strong	Biomarker	[10]
Liver and intrahepatic bile duct neoplasm	DISRQ76N	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neurofibromatosis type 1	DIS53JH9	Strong	Altered Expression	[13]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[14]
Adenoma	DIS78ZEV	Limited	Altered Expression	[15]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[16]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[15]
Hyperlipidemia	DIS61J3S	Limited	Biomarker	[17]
Hyperlipoproteinemia	DISVBLBO	Limited	Biomarker	[17]
Intestinal neoplasm	DISK0GUH	Limited	Biomarker	[15]
Obesity	DIS47Y1K	Limited	Biomarker	[18]
Temporal lobe epilepsy	DISNOPXX	Limited	Genetic Variation	[19]

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 affects the methylation of C->U-editing enzyme APOBEC-1 (APOBEC1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of C->U-editing enzyme APOBEC-1 (APOBEC1).	[21]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of C->U-editing enzyme APOBEC-1 (APOBEC1).	[22]

References

• [1] The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas.Genome Biol. 2014 Jul 31;15(7):417. doi: 10.1186/s13059-014-0417-z.
• [2] Apobec-1 increases cyclooxygenase-2 and aggravates injury in oxygen-deprived neurogenic cells and middle cerebral artery occlusion rats.Neurochem Res. 2013 Jul;38(7):1434-45. doi: 10.1007/s11064-013-1043-y. Epub 2013 Apr 23.
• [3] Corrigendum: A Novel RNA Editing Sensor Tool and a Specific Agonist Determine Neuronal Protein Expression of RNA-Edited Glycine Receptors and Identify a Genomic APOBEC1 Dimorphism as a New Genetic Risk Factor of Epilepsy.Front Mol Neurosci. 2019 Apr 24;12:103. doi: 10.3389/fnmol.2019.00103. eCollection 2019.
• [4] Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in RemoteArteries.J Am Coll Cardiol. 2018 Aug 28;72(9):1015-1026. doi: 10.1016/j.jacc.2018.06.044.
• [5] Ticagrelor induces paraoxonase-1 (PON1) and better protects hypercholesterolemic mice against atherosclerosis compared to clopidogrel.PLoS One. 2019 Jun 26;14(6):e0218934. doi: 10.1371/journal.pone.0218934. eCollection 2019.
• [6] Investigation of the Lith6 candidate genes APOBEC1 and PPARG in human gallstone disease.Liver Int. 2007 Sep;27(7):910-9. doi: 10.1111/j.1478-3231.2007.01536.x.
• [7] Apobec-1 transcription in rat colon cancer: decreased apobec-1 protein production through alterations in polysome distribution and mRNA translation associated with upstream AUGs.Biochim Biophys Acta. 2002 May 3;1575(1-3):54-62. doi: 10.1016/s0167-4781(02)00250-6.
• [8] An alternatively spliced form of apobec-1 messenger RNA is overexpressed in human colon cancer.Gastroenterology. 1998 Nov;115(5):1096-103. doi: 10.1016/s0016-5085(98)70080-0.
• [9] Absence of APOBEC-1 mediated mRNA editing in human carcinomas.Oncogene. 1999 Nov 4;18(46):6357-66. doi: 10.1038/sj.onc.1203039.
• [10] Murine APOBEC1 is a powerful mutator of retroviral and cellular RNA in vitro and in vivo.J Mol Biol. 2009 Jan 9;385(1):65-78. doi: 10.1016/j.jmb.2008.10.043. Epub 2008 Nov 1.
• [11] Low expression of the apolipoprotein B mRNA-editing transgene in mice reduces LDL levels but does not cause liver dysplasia or tumors.Arterioscler Thromb Vasc Biol. 1998 Jun;18(6):1013-20. doi: 10.1161/01.atv.18.6.1013.
• [12] Pancancer analysis identifies prognostic high-APOBEC1 expression level implicated in cancer in-frame insertions and deletions.Carcinogenesis. 2018 Mar 8;39(3):327-335. doi: 10.1093/carcin/bgy005.
• [13] C-->U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme.Am J Hum Genet. 2002 Jan;70(1):38-50. doi: 10.1086/337952. Epub 2001 Nov 27.
• [14] Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias.Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):E5425-33. doi: 10.1073/pnas.1604773113. Epub 2016 Aug 31.
• [15] Deletion of the AU-rich RNA binding protein Apobec-1 reduces intestinal tumor burden in Apc(min) mice.Cancer Res. 2007 Sep 15;67(18):8565-73. doi: 10.1158/0008-5472.CAN-07-1593.
• [16] Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA.BMC Genomics. 2019 Nov 14;20(1):858. doi: 10.1186/s12864-019-6216-x.
• [17] Effects of a thyromimetic on apolipoprotein B-100 in rats.J Mol Endocrinol. 2000 Dec;25(3):299-308. doi: 10.1677/jme.0.0250299.
• [18] Regulation of hepatic apolipoprotein B RNA editing in the genetically obese Zucker rat.Metabolism. 1996 Sep;45(9):1056-8. doi: 10.1016/s0026-0495(96)90001-3.
• [19] A Novel RNA Editing Sensor Tool and a Specific Agonist Determine Neuronal Protein Expression of RNA-Edited Glycine Receptors and Identify a Genomic APOBEC1 Dimorphism as a New Genetic Risk Factor of Epilepsy.Front Mol Neurosci. 2018 Jan 11;10:439. doi: 10.3389/fnmol.2017.00439. eCollection 2017.
• [20] 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.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [22] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.