Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJVS8CF)

• DOT Name: Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7)
• Synonyms: EC 1.14.11.-; Alkylated DNA repair protein alkB homolog 7; Spermatogenesis cell proliferation-related protein; Spermatogenesis-associated protein 11
• Gene Name: ALKBH7
• Related Disease:
  Cerebellar degeneration
  Metabolic disorder
  Advanced cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: ALKB7_HUMAN
• PDB ID: 4QKB; 4QKD; 4QKF
• EC Number: 1.14.11.-
• Pfam ID: PF13532
• Sequence:
  MAGTGLLALRTLPGPSWVRGSGPSVLSRLQDAAVVRPGFLSTAEEETLSRELEPELRRRR
  YEYDHWDAAIHGFRETEKSRWSEASRAILQRVQAAAFGPGQTLLSSVHVLDLEARGYIKP
  HVDSIKFCGATIAGLSLLSPSVMRLVHTQEPGEWLELLLEPGSLYILRGSARYDFSHEIL
  RDEESFFGERRIPRGRRISVICRSLPEGMGPGESGQPPPAC
• Function: May function as protein hydroxylase; can catalyze auto-hydroxylation at Leu-110 (in vitro), but this activity may be due to the absence of the true substrate. Required to induce programmed necrosis in response to DNA damage caused by cytotoxic alkylating agents. Acts by triggering the collapse of mitochondrial membrane potential and loss of mitochondrial function that leads to energy depletion and cell death. ALKBH7-mediated necrosis is probably required to prevent the accumulation of cells with DNA damage. Does not display DNA demethylase activity. Involved in fatty acid metabolism.
• Tissue Specificity: Widely expressed, with highest expression in pancreas, followed by spleen, prostate, ovary and placenta.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar degeneration	DISPBCM3	Definitive	Biomarker	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[3]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[3]

2 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 7, mitochondrial (ALKBH7).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[12]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Alpha-ketoglutarate-dependent dioxygenase alkB homolog 7, mitochondrial (ALKBH7).	[13]

References

• [1] ALKBH7 drives a tissue and sex-specific necrotic cell death response following alkylation-induced damage.Cell Death Dis. 2017 Jul 20;8(7):e2947. doi: 10.1038/cddis.2017.343.
• [2] The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism.J Biol Chem. 2014 Oct 3;289(40):27924-36. doi: 10.1074/jbc.M114.590505. Epub 2014 Aug 13.
• [3] 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.
• [4] 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.
• [5] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [8] 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.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.