Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSQW0BG)

• DOT Name: DNA oxidative demethylase ALKBH2 (ALKBH2)
• Synonyms: EC 1.14.11.33; Alkylated DNA repair protein alkB homolog 2; Alpha-ketoglutarate-dependent dioxygenase alkB homolog 2; Oxy DC1
• Gene Name: ALKBH2
• Related Disease:
  Adult glioblastoma
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Glioblastoma multiforme
  Neoplasm
  Transitional cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Urothelial carcinoma
  Advanced cancer
• UniProt ID: ALKB2_HUMAN
• PDB ID: 3BTX; 3BTY; 3BTZ; 3BU0; 3BUC; 3H8O; 3H8R; 3H8X; 3RZG; 3RZH; 3RZJ; 3RZK; 3RZL; 3RZM; 3S57; 3S5A; 4MG2; 4MGT
• EC Number: 1.14.11.33
• Pfam ID: PF13532
• Sequence:
  MDRFLVKGAQGGLLRKQEEQEPTGEEPAVLGGDKESTRKRPRREAPGNGGHSAGPSWRHI
  RAEGLDCSYTVLFGKAEADEIFQELEKEVEYFTGALARVQVFGKWHSVPRKQATYGDAGL
  TYTFSGLTLSPKPWIPVLERIRDHVSGVTGQTFNFVLINRYKDGCDHIGEHRDDERELAP
  GSPIASVSFGACRDFVFRHKDSRGKSPSRRVAVVRLPLAHGSLLMMNHPTNTHWYHSLPV
  RKKVLAPRVNLTFRKILLTKK
• Function: Dioxygenase that repairs alkylated nucleic acid bases by direct reversal oxidative dealkylation. Can process both double-stranded (ds) and single-stranded (ss) DNA substrates, with a strong preference for dsDNA. Uses molecular oxygen, 2-oxoglutarate and iron as cofactors to oxidize the alkyl groups that are subsequently released as aldehydes, regenerating the undamaged bases. Probes the base pair stability, locates a weakened base pair and flips the damaged base to accommodate the lesion in its active site for efficient catalysis. Repairs monoalkylated bases, specifically N1-methyladenine and N3-methylcytosine, as well as higher order alkyl adducts such as bases modified with exocyclic bridged adducts known as etheno adducts including 1,N6-ethenoadenine, 3,N4-ethenocytosine and 1,N2-ethenoguanine. Acts as a gatekeeper of genomic integrity under alkylation stress. Efficiently repairs alkylated lesions in ribosomal DNA (rDNA). These lesions can cause ss- and dsDNA strand breaks that severely impair rDNA transcription. In a response mechanism to DNA damage, associates with PCNA at replication forks to repair alkylated adducts prior to replication.
• Tissue Specificity: Detected in colon, small intestine, ovary, testis, prostate, skeletal muscle, heart, liver and urinary bladder.
• Reactome Pathway: ALKBH2 mediated reversal of alkylation damage (R-HSA-112122)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[3]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	DNA oxidative demethylase ALKBH2 (ALKBH2) decreases the response to substance of Cisplatin.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA oxidative demethylase ALKBH2 (ALKBH2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA oxidative demethylase ALKBH2 (ALKBH2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA oxidative demethylase ALKBH2 (ALKBH2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA oxidative demethylase ALKBH2 (ALKBH2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA oxidative demethylase ALKBH2 (ALKBH2).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA oxidative demethylase ALKBH2 (ALKBH2).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA oxidative demethylase ALKBH2 (ALKBH2).	[10]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the activity of DNA oxidative demethylase ALKBH2 (ALKBH2).	[13]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the activity of DNA oxidative demethylase ALKBH2 (ALKBH2).	[13]
RHEIN	DMS6IJ0	Investigative	RHEIN decreases the activity of DNA oxidative demethylase ALKBH2 (ALKBH2).	[13]
1,2,3,4,6-penta-O-galloyl-beta-D-glucose	DMTK650	Investigative	1,2,3,4,6-penta-O-galloyl-beta-D-glucose decreases the activity of DNA oxidative demethylase ALKBH2 (ALKBH2).	[13]

2 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 increases the methylation of DNA oxidative demethylase ALKBH2 (ALKBH2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA oxidative demethylase ALKBH2 (ALKBH2).	[12]

References

• [1] The DNA repair protein ALKBH2 mediates temozolomide resistance in human glioblastoma cells.Neuro Oncol. 2013 Mar;15(3):269-78. doi: 10.1093/neuonc/nos301. Epub 2012 Dec 20.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [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] 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.
• [13] Hydrolyzable Tannins Are Iron Chelators That Inhibit DNA Repair Enzyme ALKBH2. Chem Res Toxicol. 2019 Jun 17;32(6):1082-1086. doi: 10.1021/acs.chemrestox.8b00398. Epub 2019 May 28.
• [14] Down-regulation of ALKBH2 increases cisplatin sensitivity in H1299 lung cancer cells. Acta Pharmacol Sin. 2011 Mar;32(3):393-8. doi: 10.1038/aps.2010.216. Epub 2011 Jan 31.