Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW95XD4)

• DOT Name: Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12)
• Synonyms: EC 1.1.1.330; 17-beta-hydroxysteroid dehydrogenase 12; 17-beta-HSD 12; 3-ketoacyl-CoA reductase; KAR; Estradiol 17-beta-dehydrogenase 12; EC 1.1.1.62; Short chain dehydrogenase/reductase family 12C member 1
• Gene Name: HSD17B12
• UniProt ID: DHB12_HUMAN
• EC Number: 1.1.1.330; 1.1.1.62
• Pfam ID: PF00106
• Sequence:
  MESALPAAGFLYWVGAGTVAYLALRISYSLFTALRVWGVGNEAGVGPGLGEWAVVTGSTD
  GIGKSYAEELAKHGMKVVLISRSKDKLDQVSSEIKEKFKVETRTIAVDFASEDIYDKIKT
  GLAGLEIGILVNNVGMSYEYPEYFLDVPDLDNVIKKMININILSVCKMTQLVLPGMVERS
  KGAILNISSGSGMLPVPLLTIYSATKTFVDFFSQCLHEEYRSKGVFVQSVLPYFVATKLA
  KIRKPTLDKPSPETFVKSAIKTVGLQSRTNGYLIHALMGSIISNLPSWIYLKIVMNMNKS
  TRAHYLKKTKKN
• Function: Catalyzes the second of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme has a 3-ketoacyl-CoA reductase activity, reducing 3-ketoacyl-CoA to 3-hydroxyacyl-CoA, within each cycle of fatty acid elongation. Thereby, it may participate in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May also catalyze the transformation of estrone (E1) into estradiol (E2) and play a role in estrogen formation.
• Tissue Specificity: Expressed in most tissues tested. Highly expressed in the ovary and mammary. Expressed in platelets.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Steroid hormone biosynthesis (hsa00140)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway:
  Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876)
  Androgen biosynthesis (R-HSA-193048)
• BioCyc Pathway: MetaCyc:HS07581-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12) increases the chemical synthesis of Estradiol.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[6]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[7]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Very-long-chain 3-oxoacyl-CoA reductase (HSD17B12).	[10]

References

• [1] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [5] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [6] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [7] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [8] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [9] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Characterization of type 12 17beta-hydroxysteroid dehydrogenase, an isoform of type 3 17beta-hydroxysteroid dehydrogenase responsible for estradiol formation in women. Mol Endocrinol. 2006 Feb;20(2):437-43.