Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX1DWEF)

• DOT Name: (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8)
• Synonyms: EC 1.1.1.n12; 17-beta-hydroxysteroid dehydrogenase 8; 17-beta-HSD 8; HSD17B8; 3-ketoacyl- reductase alpha subunit; KAR alpha subunit; 3-oxoacyl- reductase; Estradiol 17-beta-dehydrogenase 8; EC 1.1.1.62; Protein Ke6; Ke6; Short chain dehydrogenase/reductase family 30C member 1; Testosterone 17-beta-dehydrogenase 8; EC 1.1.1.239
• Gene Name: HSD17B8
• Related Disease:
  Hepatitis B virus infection
  Breast neoplasm
  Rheumatoid arthritis
  Tuberculosis
  Neoplasm
• UniProt ID: DHB8_HUMAN
• PDB ID: 2PD6; 4CQL; 4CQM
• EC Number: 1.1.1.239; 1.1.1.62; 1.1.1.n12
• Pfam ID: PF13561
• Sequence:
  MASQLQNRLRSALALVTGAGSGIGRAVSVRLAGEGATVAACDLDRAAAQETVRLLGGPGS
  KEGPPRGNHAAFQADVSEARAARCLLEQVQACFSRPPSVVVSCAGITQDEFLLHMSEDDW
  DKVIAVNLKGTFLVTQAAAQALVSNGCRGSIINISSIVGKVGNVGQTNYAASKAGVIGLT
  QTAARELGRHGIRCNSVLPGFIATPMTQKVPQKVVDKITEMIPMGHLGDPEDVADVVAFL
  ASEDSGYITGTSVEVTGGLFM
• Function: Required for the solubility and assembly of the heterotetramer 3-ketoacyl-[acyl carrier protein] (ACP) reductase functional complex (KAR or KAR1) that forms part of the mitochondrial fatty acid synthase (mtFAS). Alpha-subunit of the KAR complex that acts as a scaffold protein required for the stability of carbonyl reductase type-4 (CBR4, beta-subunit of the KAR complex) and for its 3-ketoacyl-ACP reductase activity, thereby participating in mitochondrial fatty acid biosynthesis. Catalyzes the NAD-dependent conversion of (3R)-3-hydroxyacyl-CoA into 3-ketoacyl-CoA (3-oxoacyl-CoA) with no chain length preference; this enzymatic activity is not needed for the KAR function. Prefers (3R)-3-hydroxyacyl-CoA over (3S)-3-hydroxyacyl-CoA and displays enzymatic activity only in the presence of NAD(+). Cooperates with enoyl-CoA hydratase 1 in mitochondria, together they constitute an alternative route to the auxiliary enzyme pathways for the breakdown of Z-PUFA (cis polyunsaturated fatty acid) enoyl-esters (Probable). NAD-dependent 17-beta-hydroxysteroid dehydrogenase with highest activity towards estradiol (17beta-estradiol or E2). Has very low activity towards testosterone and dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one). Primarily an oxidative enzyme, it can switch to a reductive mode determined in the appropriate physiologic milieu and catalyze the reduction of estrone (E1) to form biologically active 17beta-estradiol.
• Tissue Specificity: Widely expressed, particularly abundant in prostate, placenta and kidney . Expressed at protein level in various tissues like brain, cerebellum, heart, lung, kidney, ovary, testis, adrenals and prostate .
• KEGG Pathway:
  Fatty acid biosynthesis (hsa00061)
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway: Fatty acyl-CoA biosynthesis (R-HSA-75105)
• BioCyc Pathway: MetaCyc:HS03575-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[3]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[5]

19 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 (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[13]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[13]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of (3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8).	[23]

References

• [1] A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population.Hum Mol Genet. 2011 Oct 1;20(19):3884-92. doi: 10.1093/hmg/ddr301. Epub 2011 Jul 12.
• [2] Expression of aromatase and 17beta-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer. An immunocytochemical study.J Steroid Biochem Mol Biol. 2006 Oct;101(2-3):136-44. doi: 10.1016/j.jsbmb.2006.06.015. Epub 2006 Aug 22.
• [3] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [4] Genetic sequencing for surveillance of drug resistance in tuberculosis in highly endemic countries: a multi-country population-based surveillance study.Lancet Infect Dis. 2018 Jun;18(6):675-683. doi: 10.1016/S1473-3099(18)30073-2. Epub 2018 Mar 21.
• [5] Genes in the HLA region indicative for head and neck squamous cell carcinoma.Mol Immunol. 2007 Feb;44(5):848-55. doi: 10.1016/j.molimm.2006.04.003. Epub 2006 Jun 5.
• [6] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.