Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXN70DV)

• DOT Name: Alkylated DNA repair protein alkB homolog 8 (ALKBH8)
• Synonyms: Probable alpha-ketoglutarate-dependent dioxygenase ABH8; S-adenosyl-L-methionine-dependent tRNA methyltransferase ABH8; tRNA (carboxymethyluridine(34)-5-O)-methyltransferase ABH8; EC 2.1.1.229
• Gene Name: ALKBH8
• Related Disease:
  Intellectual developmental disorder, autosomal recessive 71
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Intellectual disability
  Narcolepsy
  Urinary bladder cancer
  Urinary bladder neoplasm
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: ALKB8_HUMAN
• PDB ID: 2CQ2; 3THP; 3THT
• EC Number: 2.1.1.229
• Pfam ID: PF13532 ; PF09004 ; PF08241 ; PF00076
• Sequence:
  MDSNHQSNYKLSKTEKKFLRKQIKAKHTLLRHEGIETVSYATQSLVVANGGLGNGVSRNQ
  LLPVLEKCGLVDALLMPPNKPYSFARYRTTEESKRAYVTLNGKEVVDDLGQKITLYLNFV
  EKVQWKELRPQALPPGLMVVEEIISSEEEKMLLESVDWTEDTDNQNSQKSLKHRRVKHFG
  YEFHYENNNVDKDKPLSGGLPDICESFLEKWLRKGYIKHKPDQMTINQYEPGQGIPAHID
  THSAFEDEIVSLSLGSEIVMDFKHPDGIAVPVMLPRRSLLVMTGESRYLWTHGITCRKFD
  TVQASESLKSGIITSDVGDLTLSKRGLRTSFTFRKVRQTPCNCSYPLVCDSQRKETPPSF
  PESDKEASRLEQEYVHQVYEEIAGHFSSTRHTPWPHIVEFLKALPSGSIVADIGCGNGKY
  LGINKELYMIGCDRSQNLVDICRERQFQAFVCDALAVPVRSGSCDACISIAVIHHFATAE
  RRVAALQEIVRLLRPGGKALIYVWAMEQEYNKQKSKYLRGNRNSQGKKEEMNSDTSVQRS
  LVEQMRDMGSRDSASSVPRINDSQEGGCNSRQVSNSKLPVHVNRTSFYSQDVLVPWHLKG
  NPDKGKPVEPFGPIGSQDPSPVFHRYYHVFREGELEGACRTVSDVRILQSYYDQGNWCVI
  LQKA
• Function: Catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA via its methyltransferase domain. Catalyzes the last step in the formation of 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in target tRNA. Has a preference for tRNA(Arg) and tRNA(Glu), and does not bind tRNA(Lys). Binds tRNA and catalyzes the iron and alpha-ketoglutarate dependent hydroxylation of 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA via its dioxygenase domain, giving rise to 5-(S)-methoxycarbonylhydroxymethyluridine; has a preference for tRNA(Gly). Required for normal survival after DNA damage. May inhibit apoptosis and promote cell survival and angiogenesis.
• Tissue Specificity: Widely expressed, with highest expression in spleen, followed by pancreas and lung.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)
• BioCyc Pathway: MetaCyc:ENSG00000137760-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual developmental disorder, autosomal recessive 71	DIS8OP78	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[5]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[1]

7 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 Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[14]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Alkylated DNA repair protein alkB homolog 8 (ALKBH8).	[15]

References

• [1] Recessive Truncating Mutations in ALKBH8 Cause Intellectual Disability and Severe Impairment of Wobble Uridine Modification. Am J Hum Genet. 2019 Jun 6;104(6):1202-1209. doi: 10.1016/j.ajhg.2019.03.026. Epub 2019 May 9.
• [2] A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression.Cancer Res. 2009 Apr 1;69(7):3157-64. doi: 10.1158/0008-5472.CAN-08-3530. Epub 2009 Mar 17.
• [3] ALKBH8 promotes bladder cancer growth and progression through regulating the expression of survivin.Biochem Biophys Res Commun. 2016 Aug 26;477(3):413-8. doi: 10.1016/j.bbrc.2016.06.084. Epub 2016 Jun 18.
• [4] Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.J Exp Med. 2016 Oct 17;213(11):2503-2523. doi: 10.1084/jem.20160397. Epub 2016 Oct 10.
• [5] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74. doi: 10.1073/pnas.1108190108. Epub 2011 Sep 26.
• [15] 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.