Details of Drug Off-Target (DOT)

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

• DOT Name: Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE)
• Synonyms: TRH-DE; TRH-degrading ectoenzyme; EC 3.4.19.6; Pyroglutamyl-peptidase II; PAP-II; TRH-specific aminopeptidase; Thyroliberinase
• Gene Name: TRHDE
• UniProt ID: TRHDE_HUMAN
• EC Number: 3.4.19.6
• Pfam ID: PF11838 ; PF01433 ; PF17900
• Sequence:
  MALDGELGEQEEEKKKKKKKKRKKKKEEEEEEEGAEKSSSPFAAAMGEDDAALRAGSRGL
  SDPWADSVGVRPRTTERHIAVHKRLVLAFAVSLVALLAVTMLAVLLSLRFDECGASATPG
  ADGGPSGFPERGGNGSLPGSARRNHHAGGDSWQPEAGGVASPGTTSAQPPSEEEREPWEP
  WTQLRLSGHLKPLHYNLMLTAFMENFTFSGEVNVEIACRNATRYVVLHASRVAVEKVQLA
  EDRAFGAVPVAGFFLYPQTQVLVVVLNRTLDAQRNYNLKIIYNALIENELLGFFRSSYVL
  HGERRFLGVTQFSPTHARKAFPCFDEPIYKATFKISIKHQATYLSLSNMPVETSVFEEDG
  WVTDHFSQTPLMSTYYLAWAICNFTYRETTTKSGVVVRLYARPDAIRRGSGDYALHITKR
  LIEFYEDYFKVPYSLPKLDLLAVPKHPYAAMENWGLSIFVEQRILLDPSVSSISYLLDVT
  MVIVHEICHQWFGDLVTPVWWEDVWLKEGFAHYFEFVGTDYLYPGWNMEKQRFLTDVLHE
  VMLLDGLASSHPVSQEVLQATDIDRVFDWIAYKKGAALIRMLANFMGHSVFQRGLQDYLT
  IHKYGNAARNDLWNTLSEALKRNGKYVNIQEVMDQWTLQMGYPVITILGNTTAENRIIIT
  QQHFIYDISAKTKALKLQNNSYLWQIPLTIVVGNRSHVSSEAIIWVSNKSEHHRITYLDK
  GSWLLGNINQTGYFRVNYDLRNWRLLIDQLIRNHEVLSVSNRAGLIDDAFSLARAGYLPQ
  NIPLEIIRYLSEEKDFLPWHAASRALYPLDKLLDRMENYNIFNEYILKQVATTYIKLGWP
  KNNFNGSLVQASYQHEELRREVIMLACSFGNKHCHQQASTLISDWISSNRNRIPLNVRDI
  VYCTGVSLLDEDVWEFIWMKFHSTTAVSEKKILLEALTCSDDRNLLNRLLNLSLNSEVVL
  DQDAIDVIIHVARNPHGRDLAWKFFRDKWKILNTRYGEALFMNSKLISGVTEFLNTEGEL
  KELKNFMKNYDGVAAASFSRAVETVEANVRWKMLYQDELFQWLGKALRH
• Function: Specific inactivation of TRH after its release.
• Tissue Specificity: Predominantly expressed in brain.

Molecular Interaction Atlas (MIA) of This DOT

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[3]

7 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 Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[5]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[2]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Thyrotropin-releasing hormone-degrading ectoenzyme (TRHDE).	[7]

References

• [1] 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.
• [2] 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.
• [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] 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.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [7] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.