Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7RJON4)

• DOT Name: 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10)
• Synonyms: EC 1.1.1.35; 17-beta-estradiol 17-dehydrogenase; EC 1.1.1.62; 2-methyl-3-hydroxybutyryl-CoA dehydrogenase; MHBD; 3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+)); EC 1.1.1.239; 3-hydroxy-2-methylbutyryl-CoA dehydrogenase; EC 1.1.1.178; 3-hydroxyacyl-CoA dehydrogenase type II; 3alpha(or 20beta)-hydroxysteroid dehydrogenase; EC 1.1.1.53; 7-alpha-hydroxysteroid dehydrogenase; EC 1.1.1.159; Endoplasmic reticulum-associated amyloid beta-peptide-binding protein; Mitochondrial ribonuclease P protein 2; Mitochondrial RNase P protein 2; Short chain dehydrogenase/reductase family 5C member 1; Short-chain type dehydrogenase/reductase XH98G2; Type II HADH
• Gene Name: HSD17B10
• Related Disease:
  HSD10 mitochondrial disease
  Obsolete syndromic X-linked intellectual disability type 10
  HSD10 disease, infantile type
  HSD10 disease, neonatal type
• UniProt ID: HCD2_HUMAN
• PDB ID: 1SO8; 1U7T; 2O23; 7ONU
• EC Number: 1.1.1.159; 1.1.1.178; 1.1.1.239; 1.1.1.35; 1.1.1.53; 1.1.1.62
• Pfam ID: PF00106
• Sequence:
  MAAACRSVKGLVAVITGGASGLGLATAERLVGQGASAVLLDLPNSGGEAQAKKLGNNCVF
  APADVTSEKDVQTALALAKGKFGRVDVAVNCAGIAVASKTYNLKKGQTHTLEDFQRVLDV
  NLMGTFNVIRLVAGEMGQNEPDQGGQRGVIINTASVAAFEGQVGQAAYSASKGGIVGMTL
  PIARDLAPIGIRVMTIAPGLFGTPLLTSLPEKVCNFLASQVPFPSRLGDPAEYAHLVQAI
  IENPFLNGEVIRLDGAIRMQP
• Function: Mitochondrial dehydrogenase involved in pathways of fatty acid, branched-chain amino acid and steroid metabolism. Acts as (S)-3-hydroxyacyl-CoA dehydrogenase in mitochondrial fatty acid beta-oxidation, a major degradation pathway of fatty acids. Catalyzes the third step in the beta-oxidation cycle, namely the reversible conversion of (S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA. Preferentially accepts straight medium- and short-chain acyl-CoA substrates with highest efficiency for (3S)-hydroxybutanoyl-CoA. Acts as 3-hydroxy-2-methylbutyryl-CoA dehydrogenase in branched-chain amino acid catabolic pathway. Catalyzes the oxidation of 3-hydroxy-2-methylbutanoyl-CoA into 2-methyl-3-oxobutanoyl-CoA, a step in isoleucine degradation pathway. Has hydroxysteroid dehydrogenase activity toward steroid hormones and bile acids. Catalyzes the oxidation of 3alpha-, 17beta-, 20beta- and 21-hydroxysteroids and 7alpha- and 7beta-hydroxy bile acids. Oxidizes allopregnanolone/brexanolone at the 3alpha-hydroxyl group, which is known to be critical for the activation of gamma-aminobutyric acid receptors (GABAARs) chloride channel. Has phospholipase C-like activity toward cardiolipin and its oxidized species. Likely oxidizes the 2'-hydroxyl in the head group of cardiolipin to form a ketone intermediate that undergoes nucleophilic attack by water and fragments into diacylglycerol, dihydroxyacetone and orthophosphate. Has higher affinity for cardiolipin with oxidized fatty acids and may degrade these species during the oxidative stress response to protect cells from apoptosis. By interacting with intracellular amyloid-beta, it may contribute to the neuronal dysfunction associated with Alzheimer disease (AD). Essential for structural and functional integrity of mitochondria ; In addition to mitochondrial dehydrogenase activity, moonlights as a component of mitochondrial ribonuclease P, a complex that cleaves tRNA molecules in their 5'-ends. Together with TRMT10C/MRPP1, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity. The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; HSD17B10/MRPP2 acting as a non-catalytic subunit. The MRPP1-MRPP2 subcomplex also acts as a tRNA maturation platform: following 5'-end cleavage by the mitochondrial ribonuclease P complex, the MRPP1-MRPP2 subcomplex enhances the efficiency of 3'-processing catalyzed by ELAC2, retains the tRNA product after ELAC2 processing and presents the nascent tRNA to the mitochondrial CCA tRNA nucleotidyltransferase TRNT1 enzyme. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
• Tissue Specificity: Ubiquitously expressed in normal tissues but is overexpressed in neurons affected in AD.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Metabolic pathways (hsa01100)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  tRNA modification in the mitochondrion (R-HSA-6787450)
  Branched-chain amino acid catabolism (R-HSA-70895)
  rRNA processing in the mitochondrion (R-HSA-8868766)
  tRNA processing in the mitochondrion (R-HSA-6785470)
• BioCyc Pathway: MetaCyc:HS01071-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
HSD10 mitochondrial disease	DISCJYFW	Definitive	X-linked	[1]
Obsolete syndromic X-linked intellectual disability type 10	DISBSVZW	Definitive	X-linked recessive	[2]
HSD10 disease, infantile type	DIS4MPYD	Supportive	X-linked	[3]
HSD10 disease, neonatal type	DISTR78F	Supportive	X-linked	[3]

3 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 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[9]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[11]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[13]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[14]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[17]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[20]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of 3-hydroxyacyl-CoA dehydrogenase type-2 (HSD17B10).	[21]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A new neurological syndrome with mental retardation, choreoathetosis, and abnormal behavior maps to chromosome Xp11. Am J Hum Genet. 1999 Nov;65(5):1406-12. doi: 10.1086/302638.
• [3] HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. J Inherit Metab Dis. 2012 Jan;35(1):81-9. doi: 10.1007/s10545-011-9415-4. Epub 2011 Nov 30.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [8] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [9] 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.
• [10] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [11] 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.
• [12] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [13] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [14] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [15] 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.
• [16] 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.
• [17] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [18] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.