Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTADGU5D)

DOT Name Nucleic acid dioxygenase ALKBH1 (ALKBH1)
Synonyms
EC 1.14.11.-; Alkylated DNA repair protein alkB homolog 1; Alpha-ketoglutarate-dependent dioxygenase ABH1; DNA 6mA demethylase; DNA N6-methyl adenine demethylase ALKBH1; EC 1.14.11.51; DNA lyase ABH1; EC 4.2.99.18; DNA oxidative demethylase ALKBH1; EC 1.14.11.33; mRNA N(3)-methylcytidine demethylase; EC 1.14.11.-
Gene Name ALKBH1
Related Disease
Duodenal ulcer ( )
Advanced cancer ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Autoimmune disease ( )
Bladder cancer ( )
Carcinoma ( )
Cardiovascular disease ( )
Diabetic kidney disease ( )
Gastric cancer ( )
Head and neck cancer ( )
Head and neck carcinoma ( )
Lung cancer ( )
Lung carcinoma ( )
Metastatic malignant neoplasm ( )
Multiple sclerosis ( )
Obstructive lung disease ( )
Peptic ulcer ( )
Prostate cancer ( )
Prostate carcinoma ( )
Stomach cancer ( )
Transitional cell carcinoma ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Von willebrand disease ( )
Filarial disease ( )
High blood pressure ( )
Adult glioblastoma ( )
Glioblastoma multiforme ( )
Leukemia ( )
Lymphoma ( )
Meningococcal disease ( )
Neoplasm ( )
Nervous system disease ( )
Ocular hypertension ( )
UniProt ID
ALKB1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
6IE2; 6IE3
EC Number
1.14.11.-; 1.14.11.33; 1.14.11.51; 4.2.99.18
Pfam ID
PF13532
Sequence
MGKMAAAVGSVATLATEPGEDAFRKLFRFYRQSRPGTADLEGVIDFSAAHAARGKGPGAQ
KVIKSQLNVSSVSEQNAYRAGLQPVSKWQAYGLKGYPGFIFIPNPFLPGYQWHWVKQCLK
LYSQKPNVCNLDKHMSKEETQDLWEQSKEFLRYKEATKRRPRSLLEKLRWVTVGYHYNWD
SKKYSADHYTPFPSDLGFLSEQVAAACGFEDFRAEAGILNYYRLDSTLGIHVDRSELDHS
KPLLSFSFGQSAIFLLGGLQRDEAPTAMFMHSGDIMIMSGFSRLLNHAVPRVLPNPEGEG
LPHCLEAPLPAVLPRDSMVEPCSMEDWQVCASYLKTARVNMTVRQVLATDQNFPLEPIED
EKRDISTEGFCHLDDQNSEVKRARINPDS
Function
Dioxygenase that acts as on nucleic acids, such as DNA and tRNA. Requires molecular oxygen, alpha-ketoglutarate and iron. A number of activities have been described for this dioxygenase, but recent results suggest that it mainly acts as on tRNAs and mediates their demethylation or oxidation depending on the context and subcellular compartment. Mainly acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs, with a preference for N(1)-methyladenine at position 58 (m1A58) present on a stem loop structure of tRNAs. Acts as a regulator of translation initiation and elongation in response to glucose deprivation: regulates both translation initiation, by mediating demethylation of tRNA(Met), and translation elongation, N(1)-methyladenine-containing tRNAs being preferentially recruited to polysomes to promote translation elongation. In mitochondrion, specifically interacts with mt-tRNA(Met) and mediates oxidation of mt-tRNA(Met) methylated at cytosine(34) to form 5-formylcytosine (f(5)c) at this position. mt-tRNA(Met) containing the f(5)c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation. Specifically demethylates DNA methylated on the 6th position of adenine (N(6)-methyladenosine) DNA. N(6)-methyladenosine (m6A) DNA is present at some L1 elements in embryonic stem cells and probably promotes their silencing. Demethylates mRNAs containing N(3)-methylcytidine modification. Also able to repair alkylated single-stranded DNA by oxidative demethylation, but with low activity. Also has DNA lyase activity and introduces double-stranded breaks at abasic sites: cleaves both single-stranded DNA and double-stranded DNA at abasic sites, with the greatest activity towards double-stranded DNA with two abasic sites. DNA lyase activity does not require alpha-ketboglutarate and iron and leads to the formation of an irreversible covalent protein-DNA adduct with the 5' DNA product. DNA lyase activity is not required during base excision repair and class switch recombination of the immunoglobulin heavy chain during B lymphocyte activation. May play a role in placental trophoblast lineage differentiation.
Tissue Specificity Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Duodenal ulcer DISNHHCN Definitive Biomarker [1]
Advanced cancer DISAT1Z9 Strong Biomarker [2]
Arteriosclerosis DISK5QGC Strong Biomarker [3]
Atherosclerosis DISMN9J3 Strong Biomarker [3]
Autoimmune disease DISORMTM Strong Biomarker [4]
Bladder cancer DISUHNM0 Strong Biomarker [5]
Carcinoma DISH9F1N Strong Biomarker [6]
Cardiovascular disease DIS2IQDX Strong Biomarker [7]
Diabetic kidney disease DISJMWEY Strong Biomarker [8]
Gastric cancer DISXGOUK Strong Altered Expression [9]
Head and neck cancer DISBPSQZ Strong Altered Expression [2]
Head and neck carcinoma DISOU1DS Strong Altered Expression [2]
Lung cancer DISCM4YA Strong Altered Expression [10]
Lung carcinoma DISTR26C Strong Altered Expression [11]
Metastatic malignant neoplasm DIS86UK6 Strong Altered Expression [12]
Multiple sclerosis DISB2WZI Strong Biomarker [13]
Obstructive lung disease DIS4IIDZ Strong Genetic Variation [14]
Peptic ulcer DISL8XZI Strong Biomarker [15]
Prostate cancer DISF190Y Strong Biomarker [16]
Prostate carcinoma DISMJPLE Strong Biomarker [16]
Stomach cancer DISKIJSX Strong Altered Expression [9]
Transitional cell carcinoma DISWVVDR Strong Biomarker [6]
Urinary bladder cancer DISDV4T7 Strong Biomarker [5]
Urinary bladder neoplasm DIS7HACE Strong Altered Expression [17]
Von willebrand disease DIS3TZCH Strong Genetic Variation [18]
Filarial disease DISWBRRN moderate Biomarker [19]
High blood pressure DISY2OHH moderate Biomarker [20]
Adult glioblastoma DISVP4LU Limited Biomarker [21]
Glioblastoma multiforme DISK8246 Limited Biomarker [21]
Leukemia DISNAKFL Limited Biomarker [22]
Lymphoma DISN6V4S Limited Biomarker [22]
Meningococcal disease DISGDM2Z Limited Biomarker [23]
Neoplasm DISZKGEW Limited Altered Expression [9]
Nervous system disease DISJ7GGT Limited Biomarker [24]
Ocular hypertension DISC2BT9 Limited Biomarker [25]
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⏷ Show the Full List of 35 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
5 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Nucleic acid dioxygenase ALKBH1 (ALKBH1). [26]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Nucleic acid dioxygenase ALKBH1 (ALKBH1). [27]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Nucleic acid dioxygenase ALKBH1 (ALKBH1). [28]
Methotrexate DM2TEOL Approved Methotrexate affects the expression of Nucleic acid dioxygenase ALKBH1 (ALKBH1). [29]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of Nucleic acid dioxygenase ALKBH1 (ALKBH1). [30]
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References

1 Hereditary aspects of duodenal ulceration: pepsin 1 secretion in relation to ABO blood groups and ABH secretor status.J Med Genet. 1979 Dec;16(6):423-7. doi: 10.1136/jmg.16.6.423.
2 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.
3 Association of N(6)-methyladenine DNA with plaque progression in atherosclerosis via myocardial infarction-associated transcripts.Cell Death Dis. 2019 Dec 4;10(12):909. doi: 10.1038/s41419-019-2152-6.
4 Depletion of CD52-positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune-tolerance promoting CD8 T-cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis.Immunology. 2017 Apr;150(4):444-455. doi: 10.1111/imm.12696. Epub 2017 Jan 3.
5 ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression.Cancer Sci. 2013 Mar;104(3):321-7. doi: 10.1111/cas.12089. Epub 2013 Feb 14.
6 Blood group ABH-related antigens in normal and malignant bladder urothelium: possible structural basis for the deletion of type-2 chain ABH antigens in invasive carcinomas.Int J Cancer. 1989 May 15;43(5):774-80. doi: 10.1002/ijc.2910430505.
7 ABH and Lewis histo-blood group antigens, a model for the meaning of oligosaccharide diversity in the face of a changing world.Biochimie. 2001 Jul;83(7):565-73. doi: 10.1016/s0300-9084(01)01321-9.
8 Xiao-Shen-Formula, a Traditional Chinese Medicine, Improves Glomerular Hyper-Filtration in Diabetic Nephropathy via Inhibiting Arginase Activation and Heparanase Expression.Front Physiol. 2018 Sep 26;9:1195. doi: 10.3389/fphys.2018.01195. eCollection 2018.
9 Expression of Demethylase Genes, FTO and ALKBH1, Is Associated with Prognosis of Gastric Cancer.Dig Dis Sci. 2019 Jun;64(6):1503-1513. doi: 10.1007/s10620-018-5452-2. Epub 2019 Jan 14.
10 Effects of ABO and FUT2 genetic transcription absence on ABH histo-blood group antigen expression in lung cancer patients.Asian Pac J Cancer Prev. 2011;12(12):3201-6.
11 N 6-Hydroxymethyladenine: a hydroxylation derivative of N6-methyladenine in genomic DNA of mammals.Nucleic Acids Res. 2019 Feb 20;47(3):1268-1277. doi: 10.1093/nar/gky1218.
12 Blood type B antigen modulates cell migration through regulating cdc42 expression and activity in HaCaT cells.J Cell Physiol. 2013 Nov;228(11):2243-51. doi: 10.1002/jcp.24393.
13 Multiple sclerosis animal models: a clinical and histopathological perspective.Brain Pathol. 2017 Mar;27(2):123-137. doi: 10.1111/bpa.12454. Epub 2017 Jan 11.
14 Genetic-environmental interactions in chronic airways obstruction.Int J Epidemiol. 1986 Mar;15(1):65-72. doi: 10.1093/ije/15.1.65.
15 Interrelation between ABH blood group 0, Lewis(B) blood group antigen, Helicobacter pylori infection, and occurrence of peptic ulcer.Z Gastroenterol. 2002 May;40(5):273-6. doi: 10.1055/s-2002-30115.
16 ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding.PLoS Comput Biol. 2017 Feb 23;13(2):e1005345. doi: 10.1371/journal.pcbi.1005345. eCollection 2017 Feb.
17 Loss of ABH antigen expression in bladder cancer is not caused by loss of heterozygosity of the ABO locus.Int J Cancer. 1995 Nov 3;63(3):341-4. doi: 10.1002/ijc.2910630306.
18 No evidence for a direct effect of von Willebrand factor's ABH blood group antigens on von Willebrand factor clearance.J Thromb Haemost. 2015 Apr;13(4):592-600. doi: 10.1111/jth.12867. Epub 2015 Mar 11.
19 The association of blood groups, ABH secretion, haptoglobins and hemoglobins with filariasis.Hum Hered. 1976;26(2):105-9. doi: 10.1159/000152789.
20 Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition.Front Physiol. 2018 Jul 24;9:901. doi: 10.3389/fphys.2018.00901. eCollection 2018.
21 N(6)-methyladenine DNA Modification in Glioblastoma.Cell. 2018 Nov 15;175(5):1228-1243.e20. doi: 10.1016/j.cell.2018.10.006. Epub 2018 Nov 1.
22 Red cell ABH antigens in leukaemias and lymphomas.Vox Sang. 1978 Sep;35(3):154-9. doi: 10.1111/j.1423-0410.1978.tb02915.x.
23 ABH secretor status, as judged by the Lewis phenotypes, in Norwegian survivors from meningococcal disease.APMIS. 1993 Oct;101(10):791-4. doi: 10.1111/j.1699-0463.1993.tb00181.x.
24 Biozzi mice: of mice and human neurological diseases.J Neuroimmunol. 2005 Aug;165(1-2):1-10. doi: 10.1016/j.jneuroim.2005.04.010.
25 Blood groups as genetic markers in glaucoma.Br J Ophthalmol. 1988 Apr;72(4):270-3. doi: 10.1136/bjo.72.4.270.
26 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.
27 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.
28 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
29 Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
30 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.