Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS1CD9Z)

DOT Name	Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3)
Synonyms	EC 1.14.11.33; EC 1.14.11.54; Alkylated DNA repair protein alkB homolog 3; hABH3; DEPC-1; Prostate cancer antigen 1
Gene Name	ALKBH3
Related Disease	Carcinoma ( ) Advanced cancer ( ) Anemia ( ) Benign prostatic hyperplasia ( ) Bladder cancer ( ) Brain neoplasm ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Castration-resistant prostate carcinoma ( ) Hairy cell leukaemia ( ) Head-neck squamous cell carcinoma ( ) Lung cancer ( ) Neoplasm ( ) Pancreatic cancer ( ) Plasma cell myeloma ( ) Prostate cancer ( ) Prostate carcinoma ( ) Prostate neoplasm ( ) Transitional cell carcinoma ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Urothelial carcinoma ( ) Encephalitis ( ) Hepatocellular carcinoma ( ) Lung adenocarcinoma ( ) Lung carcinoma ( ) Non-small-cell lung cancer ( ) Pneumocystis pneumonia ( )
UniProt ID	ALKB3_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2IUW
EC Number	1.14.11.33; 1.14.11.54
Pfam ID	PF13532
Sequence	MEEKRRRARVQGAWAAPVKSQAIAQPATTAKSHLHQKPGQTWKNKEHHLSDREFVFKEPQ QVVRRAPEPRVIDREGVYEISLSPTGVSRVCLYPGFVDVKEADWILEQLCQDVPWKQRTG IREDITYQQPRLTAWYGELPYTYSRITMEPNPHWHPVLRTLKNRIEENTGHTFNSLLCNL YRNEKDSVDWHSDDEPSLGRCPIIASLSFGATRTFEMRKKPPPEENGDYTYVERVKIPLD HGTLLIMEGATQADWQHRVPKEYHSREPRVNLTFRTVYPDPRGAPW
Function	Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A). Repairs alkylated DNA containing 1-methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation. Has a strong preference for single-stranded DNA. Able to process alkylated m3C within double-stranded regions via its interaction with ASCC3, which promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3. Can repair exocyclic 3,N4-ethenocytosine adducs in single-stranded DNA. Also acts on RNA. Demethylates N(1)-methyladenosine (m1A) RNA, an epigenetic internal modification of messenger RNAs (mRNAs) highly enriched within 5'-untranslated regions (UTRs) and in the vicinity of start codons. Requires molecular oxygen, alpha-ketoglutarate and iron.
Tissue Specificity	Ubiquitous. Detected in heart, pancreas, skeletal muscle, thymus, testis, ovary, spleen, prostate, small intestine, peripheral blood leukocytes, urinary bladder and colon.
Reactome Pathway	ALKBH3 mediated reversal of alkylation damage (R-HSA-112126 )

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anemia	DISTVL0C	Strong	Biomarker	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[6]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[4]
Hairy cell leukaemia	DISTD2E5	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Pancreatic cancer	DISJC981	Strong	Biomarker	[11]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[14]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[1]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[1]
Encephalitis	DISLD1RL	moderate	Genetic Variation	[15]
Hepatocellular carcinoma	DIS0J828	Disputed	Biomarker	[10]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[16]
Lung carcinoma	DISTR26C	Limited	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[16]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[17]
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⏷ Show the Full List of 29 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

2 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 Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3).	[20]
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4 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 Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3).	[23]
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References

1	ALKBH3 contributes to survival and angiogenesis of human urothelial carcinoma cells through NADPH oxidase and tweak/Fn14/VEGF signals.Clin Cancer Res. 2012 Oct 1;18(19):5247-55. doi: 10.1158/1078-0432.CCR-12-0955. Epub 2012 Jul 31.
2	Human ALKBH3-induced m(1)A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells.Biochim Biophys Acta Gene Regul Mech. 2019 Jan;1862(1):35-46. doi: 10.1016/j.bbagrm.2018.10.008. Epub 2018 Oct 17.
3	Plasma advanced oxidative protein products are associated with anti-oxidative stress pathway genes and malaria in a longitudinal cohort.Malar J. 2014 Apr 3;13:134. doi: 10.1186/1475-2875-13-134.
4	anti-tumor effect of AlkB homolog 3 knockdown in hormone- independent prostate cancer cells.Curr Cancer Drug Targets. 2012 Sep;12(7):847-56. doi: 10.2174/156800912802429283.
5	Pediatric brain tumors: mutations of two dioxygenases (hABH2 and hABH3) that directly repair alkylation damage.J Neurooncol. 2009 Sep;94(2):195-201. doi: 10.1007/s11060-009-9837-0. Epub 2009 Mar 17.
6	CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.BMC Cancer. 2017 Jul 5;17(1):469. doi: 10.1186/s12885-017-3453-8.
7	Hairy cell leukemia: a tumor of pre-plasma cells.Blood. 1985 Mar;65(3):620-9.
8	ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy.Sci Rep. 2019 Sep 13;9(1):13249. doi: 10.1038/s41598-019-49550-x.
9	TP53 gene status is a critical determinant of phenotypes induced by ALKBH3 knockdown in non-small cell lung cancers.Biochem Biophys Res Commun. 2017 Jun 24;488(2):285-290. doi: 10.1016/j.bbrc.2017.05.024. Epub 2017 May 4.
10	Association of AlkB homolog 3 expression with tumor recurrence and unfavorable prognosis in hepatocellular carcinoma.J Gastroenterol Hepatol. 2018 Feb 7. doi: 10.1111/jgh.14117. Online ahead of print.
11	PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis.Cancer Res. 2012 Sep 15;72(18):4829-39. doi: 10.1158/0008-5472.CAN-12-0328. Epub 2012 Jul 23.
12	Selective expression of CD45 isoforms defines CALLA+ monoclonal B-lineage cells in peripheral blood from myeloma patients as late stage B cells.Blood. 1991 Aug 1;78(3):711-9.
13	Fluorescence Monitoring of the Oxidative Repair of DNA Alkylation Damage by ALKBH3, a Prostate Cancer Marker.J Am Chem Soc. 2016 Mar 23;138(11):3647-50. doi: 10.1021/jacs.6b00986. Epub 2016 Mar 15.
14	Prostate cancer antigen-1 as a potential novel marker for prostate cancer.Asian J Androl. 2007 Nov;9(6):821-6. doi: 10.1111/j.1745-7262.2007.00279.x.
15	Cerebrospinal fluid T cell frequency is age-related: a case-control study of 435 children with inflammatory and non-inflammatory neurological disorders.Clin Exp Immunol. 2018 Jul;193(1):103-112. doi: 10.1111/cei.13122. Epub 2018 Mar 24.
16	ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer.Br J Cancer. 2011 Feb 15;104(4):700-6. doi: 10.1038/sj.bjc.6606012. Epub 2011 Feb 1.
17	Immunization with Pneumocystis Cross-Reactive Antigen 1 (Pca1) Protects Mice against Pneumocystis Pneumonia and Generates Antibody to Pneumocystis jirovecii.Infect Immun. 2017 Mar 23;85(4):e00850-16. doi: 10.1128/IAI.00850-16. Print 2017 Apr.
18	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.
19	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.
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	Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
22	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.
23	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.