Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8733D7)

• DOT Name: Peroxisomal multifunctional enzyme type 2 (HSD17B4)
• Synonyms: MFE-2; 17-beta-hydroxysteroid dehydrogenase 4; 17-beta-HSD 4; D-bifunctional protein; DBP; Multifunctional protein 2; MFP-2; Short chain dehydrogenase/reductase family 8C member 1
• Gene Name: HSD17B4
• Related Disease:
  D-bifunctional protein deficiency
  Perrault syndrome
  Perrault syndrome 1
• UniProt ID: DHB4_HUMAN
• PDB ID: 1IKT; 1S9C; 1ZBQ; 6Z1W; 6Z1X; 8AF2; 8AF3
• EC Number: 1.1.1.n12; 4.2.1.107; 4.2.1.119
• Pfam ID: PF00106 ; PF01575 ; PF02036
• Sequence:
  MGSPLRFDGRVVLVTGAGAGLGRAYALAFAERGALVVVNDLGGDFKGVGKGSLAADKVVE
  EIRRRGGKAVANYDSVEEGEKVVKTALDAFGRIDVVVNNAGILRDRSFARISDEDWDIIH
  RVHLRGSFQVTRAAWEHMKKQKYGRIIMTSSASGIYGNFGQANYSAAKLGLLGLANSLAI
  EGRKSNIHCNTIAPNAGSRMTQTVMPEDLVEALKPEYVAPLVLWLCHESCEENGGLFEVG
  AGWIGKLRWERTLGAIVRQKNHPMTPEAVKANWKKICDFENASKPQSIQESTGSIIEVLS
  KIDSEGGVSANHTSRATSTATSGFAGAIGQKLPPFSYAYTELEAIMYALGVGASIKDPKD
  LKFIYEGSSDFSCLPTFGVIIGQKSMMGGGLAEIPGLSINFAKVLHGEQYLELYKPLPRA
  GKLKCEAVVADVLDKGSGVVIIMDVYSYSEKELICHNQFSLFLVGSGGFGGKRTSDKVKV
  AVAIPNRPPDAVLTDTTSLNQAALYRLSGDWNPLHIDPNFASLAGFDKPILHGLCTFGFS
  ARRVLQQFADNDVSRFKAIKARFAKPVYPGQTLQTEMWKEGNRIHFQTKVQETGDIVISN
  AYVDLAPTSGTSAKTPSEGGKLQSTFVFEEIGRRLKDIGPEVVKKVNAVFEWHITKGGNI
  GAKWTIDLKSGSGKVYQGPAKGAADTTIILSDEDFMEVVLGKLDPQKAFFSGRLKARGNI
  MLSQKLQMILKDYAKL
• Function: Bifunctional enzyme acting on the peroxisomal fatty acid beta-oxidation pathway. Catalyzes two of the four reactions in fatty acid degradation: hydration of 2-enoyl-CoA (trans-2-enoyl-CoA) to produce (3R)-3-hydroxyacyl-CoA, and dehydrogenation of (3R)-3-hydroxyacyl-CoA to produce 3-ketoacyl-CoA (3-oxoacyl-CoA), which is further metabolized by SCPx. Can use straight-chain and branched-chain fatty acids, as well as bile acid intermediates as substrates.
• Tissue Specificity: Present in many tissues with highest concentrations in liver, heart, prostate and testis.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
  Peroxisome (hsa04146)
• Reactome Pathway:
  alpha-linolenic acid (ALA) metabolism (R-HSA-2046106)
  Beta-oxidation of pristanoyl-CoA (R-HSA-389887)
  Beta-oxidation of very long chain fatty acids (R-HSA-390247)
  Peroxisomal protein import (R-HSA-9033241)
  TYSND1 cleaves peroxisomal proteins (R-HSA-9033500)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
• BioCyc Pathway: MetaCyc:HS05792-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
D-bifunctional protein deficiency	DISMU0DP	Definitive	Autosomal recessive	[1]
Perrault syndrome	DISG2YOV	Definitive	Autosomal recessive	[1]
Perrault syndrome 1	DISP3IK3	Strong	Autosomal recessive	[2]

This DOT Affected the Biotransformations of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Peroxisomal multifunctional enzyme type 2 (HSD17B4) increases the chemical synthesis of Estradiol.	[22]
Estrone	DM5T6US	Approved	Peroxisomal multifunctional enzyme type 2 (HSD17B4) increases the chemical synthesis of Estrone.	[22]
Prasterone	DM67VKL	Approved	Peroxisomal multifunctional enzyme type 2 (HSD17B4) increases the chemical synthesis of Prasterone.	[22]
HE2100	DMCP2KH	Discontinued in Phase 1	Peroxisomal multifunctional enzyme type 2 (HSD17B4) increases the chemical synthesis of HE2100.	[22]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Peroxisomal multifunctional enzyme type 2 (HSD17B4) affects the response to substance of Paclitaxel.	[23]
BADGE	DMCK5DG	Investigative	Peroxisomal multifunctional enzyme type 2 (HSD17B4) affects the response to substance of BADGE.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[13]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[14]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[19]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[20]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[15]
2-bromophenol	DM6JDIY	Investigative	2-bromophenol increases the expression of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[21]

1 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 Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[8]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Peroxisomal multifunctional enzyme type 2 (HSD17B4).	[17]

References

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• [2] Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing. Neurology. 2014 Mar 18;82(11):963-8. doi: 10.1212/WNL.0000000000000219. Epub 2014 Feb 19.
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• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
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• [14] 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.
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• [17] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
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• [22] Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab. 2005 Sep;16(7):327-33.
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