Details of Drug Off-Target (DOT)

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

• DOT Name: Aldo-keto reductase family 1 member B15 (AKR1B15)
• Synonyms: EC 1.1.1.-; EC 1.1.1.300; EC 1.1.1.54; Estradiol 17-beta-dehydrogenase AKR1B15; Farnesol dehydrogenase; EC 1.1.1.216; Testosterone 17beta-dehydrogenase; EC 1.1.1.64
• Gene Name: AKR1B15
• UniProt ID: AK1BF_HUMAN
• EC Number: 1.1.1.-; 1.1.1.216; 1.1.1.300; 1.1.1.54; 1.1.1.64
• Pfam ID: PF00248
• Sequence:
  MATFVELSTKAKMPIVGLGTWRSLLGKVKEAVKVAIDAEYRHIDCAYFYENQHEVGEAIQ
  EKIQEKAVMREDLFIVSKVWPTFFERPLVRKAFEKTLKDLKLSYLDVYLIHWPQGFKTGD
  DFFPKDDKGNMISGKGTFLDAWEAMEELVDEGLVKALGVSNFNHFQIERLLNKPGLKYKP
  VTNQVECHPYLTQEKLIQYCHSKGITVTAYSPLGSPDRPWAKPEDPSLLEDPKIKEIAAK
  HKKTTAQVLIRFHIQRNVTVIPKSMTPAHIVENIQVFDFKLSDEEMATILSFNRNWRAFD
  FKEFSHLEDFPFDAEY
• Function: [Isoform 1]: Catalyzes the NADPH-dependent reduction of a variety of carbonyl substrates, like aromatic aldehydes, alkenals, ketones and alpha-dicarbonyl compounds. In addition, catalyzes the reduction of androgens and estrogens with high positional selectivity (shows 17-beta-hydroxysteroid dehydrogenase activity) as well as 3-keto-acyl-CoAs. Displays strong enzymatic activity toward all-trans-retinal and 9-cis-retinal. May play a physiological role in retinoid metabolism ; [Isoform 2]: No oxidoreductase activity observed with the tested substrates.
• Tissue Specificity: Widely expressed. Expressed at highest levels in steroid-sensitive tissues, such as placenta, testis and adipose tissue.
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Fructose and mannose metabolism (hsa00051)
  Galactose metabolism (hsa00052)
  Glycerolipid metabolism (hsa00561)
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Estrogen biosynthesis (R-HSA-193144)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
2,3-dihydroxypropanal	DMOWNB4	Investigative	Aldo-keto reductase family 1 member B15 (AKR1B15) increases the metabolism of 2,3-dihydroxypropanal.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Aldo-keto reductase family 1 member B15 (AKR1B15).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Aldo-keto reductase family 1 member B15 (AKR1B15).	[2]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Aldo-keto reductase family 1 member B15 (AKR1B15).	[4]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Aldo-keto reductase family 1 member B15 (AKR1B15).	[5]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Aldo-keto reductase family 1 member B15 (AKR1B15).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aldo-keto reductase family 1 member B15 (AKR1B15).	[7]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Aldo-keto reductase family 1 member B15 (AKR1B15).	[8]

2 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 Aldo-keto reductase family 1 member B15 (AKR1B15).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Aldo-keto reductase family 1 member B15 (AKR1B15).	[9]

References

• [1] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] 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.
• [4] 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.
• [5] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [6] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [9] 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.
• [10] Functional expression of novel human and murine AKR1B genes. Chem Biol Interact. 2011 May 30;191(1-3):177-84.