Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRWRA1J)

• DOT Name: Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (ALKBH4)
• Synonyms: Alkylated DNA repair protein alkB homolog 4; DNA N6-methyl adenine demethylase ALKBH4; EC 1.14.11.51; Lysine-specific demethylase ALKBH4; EC 1.14.11.-
• Gene Name: ALKBH4
• UniProt ID: ALKB4_HUMAN
• EC Number: 1.14.11.-; 1.14.11.51
• Sequence:
  MAAAAAETPEVLRECGCKGIRTCLICERQRGSDPPWELPPAKTYRFIYCSDTGWAVGTEE
  SDFEGWAFPFPGVMLIEDFVTREEEAELVRLMDRDPWKLSQSGRRKQDYGPKVNFRKQKL
  KTEGFCGLPSFSREVVRRMGLYPGLEGFRPVEQCNLDYCPERGSAIDPHLDDAWLWGERL
  VSLNLLSPTVLSMCREAPGSLLLCSAPSAAPEALVDSVIAPSRSVLCQEVEVAIPLPARS
  LLVLTGAARHQWKHAIHRRHIEARRVCVTFRELSAEFGPGGRQQELGQELLRIALSFQGR
  PV
• Function: Dioxygenase that mediates demethylation of actin monomethylated at 'Lys-84' (K84me1), thereby acting as a regulator of actomyosin-processes. Demethylation of actin K84me1 is required for maintaining actomyosin dynamics supporting normal cleavage furrow ingression during cytokinesis and cell migration. In addition to proteins, also demethylates DNA: specifically demethylates DNA methylated on the 6th position of adenine (N(6)-methyladenosine) DNA, thereby regulating Polycomb silencing.
• Tissue Specificity: Widely expressed, with highest expression in pancreas, ovary and spleen.

Molecular Interaction Atlas (MIA) of This DOT

1 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 4 (ALKBH4).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (ALKBH4).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (ALKBH4).	[3]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (ALKBH4).	[4]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (ALKBH4).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (ALKBH4).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 4 (ALKBH4).	[7]

References

• [1] 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.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [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.