Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3PW10X)

• DOT Name: RNA demethylase ALKBH5 (ALKBH5)
• Synonyms: EC 1.14.11.53; Alkylated DNA repair protein alkB homolog 5; Alpha-ketoglutarate-dependent dioxygenase alkB homolog 5
• Gene Name: ALKBH5
• UniProt ID: ALKB5_HUMAN
• PDB ID: 4NJ4; 4NRM; 4NRO; 4NRP; 4NRQ; 4O61; 4O7X; 4OCT; 7V4G; 7WKV; 7WL0
• EC Number: 1.14.11.53
• Pfam ID: PF13532
• Sequence:
  MAAASGYTDLREKLKSMTSRDNYKAGSREAAAAAAAAVAAAAAAAAAAEPYPVSGAKRKY
  QEDSDPERSDYEEQQLQKEEEARKVKSGIRQMRLFSQDECAKIEARIDEVVSRAEKGLYN
  EHTVDRAPLRNKYFFGEGYTYGAQLQKRGPGQERLYPPGDVDEIPEWVHQLVIQKLVEHR
  VIPEGFVNSAVINDYQPGGCIVSHVDPIHIFERPIVSVSFFSDSALCFGCKFQFKPIRVS
  EPVLSLPVRRGSVTVLSGYAADEITHCIRPQDIKERRAVIILRKTRLDAPRLETKSLSSS
  VLPPSYASDRLSGNNRDPALKPKRSHRKADPDAAHRPRILEMDKEENRRSVLLPTHRRRG
  SFSSENYWRKSYESSEDCSEAAGSPARKVKMRRH
• Function: Dioxygenase that demethylates RNA by oxidative demethylation: specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Can also demethylate N(6)-methyladenosine in single-stranded DNA (in vitro). Requires molecular oxygen, alpha-ketoglutarate and iron. Demethylation of m6A mRNA affects mRNA processing and export. Required for the late meiotic and haploid phases of spermatogenesis by mediating m6A demethylation in spermatocytes and round spermatids: m6A demethylation of target transcripts is required for correct splicing and the production of longer 3'-UTR mRNAs in male germ cells.
• Tissue Specificity: Widely expressed, with highest expression in lung, followed by testis, pancreas, spleen and ovary.
• Reactome Pathway: Reversal of alkylation damage by DNA dioxygenases (R-HSA-73943)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of RNA demethylase ALKBH5 (ALKBH5).	[1]
Marinol	DM70IK5	Approved	Marinol decreases the expression of RNA demethylase ALKBH5 (ALKBH5).	[2]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RNA demethylase ALKBH5 (ALKBH5).	[3]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of RNA demethylase ALKBH5 (ALKBH5).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of RNA demethylase ALKBH5 (ALKBH5).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RNA demethylase ALKBH5 (ALKBH5).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RNA demethylase ALKBH5 (ALKBH5).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of RNA demethylase ALKBH5 (ALKBH5).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RNA demethylase ALKBH5 (ALKBH5).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA demethylase ALKBH5 (ALKBH5).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of RNA demethylase ALKBH5 (ALKBH5).	[8]

References

• [1] Role of N6-methyladenosine RNA modification in the imbalanced inflammatory homeostasis of arsenic-induced skin lesions. Environ Toxicol. 2022 Aug;37(8):1831-1839. doi: 10.1002/tox.23530. Epub 2022 Apr 1.
• [2] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [3] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [4] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [5] 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.
• [6] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [7] 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.
• [8] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [9] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.