Details of Drug Off-Target (DOT)

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

• DOT Name: Prostaglandin reductase 2 (PTGR2)
• Synonyms: PRG-2; EC 1.3.1.48; 15-oxoprostaglandin 13-reductase; Zinc-binding alcohol dehydrogenase domain-containing protein 1
• Gene Name: PTGR2
• Related Disease:
  Cystic fibrosis
  Gastric cancer
  Multiple sclerosis
  Pancreatic cancer
  Stomach cancer
• UniProt ID: PTGR2_HUMAN
• PDB ID: 2VNA; 2W4Q; 2W98; 2ZB4; 2ZB7; 2ZB8
• EC Number: 1.3.1.48
• Pfam ID: PF16884 ; PF00107
• Sequence:
  MIVQRVVLNSRPGKNGNPVAENFRMEEVYLPDNINEGQVQVRTLYLSVDPYMRCRMNEDT
  GTDYITPWQLSQVVDGGGIGIIEESKHTNLTKGDFVTSFYWPWQTKVILDGNSLEKVDPQ
  LVDGHLSYFLGAIGMPGLTSLIGIQEKGHITAGSNKTMVVSGAAGACGSVAGQIGHFLGC
  SRVVGICGTHEKCILLTSELGFDAAINYKKDNVAEQLRESCPAGVDVYFDNVGGNISDTV
  ISQMNENSHIILCGQISQYNKDVPYPPPLSPAIEAIQKERNITRERFLVLNYKDKFEPGI
  LQLSQWFKEGKLKIKETVINGLENMGAAFQSMMTGGNIGKQIVCISEEISL
• Function: Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2. Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Arachidonic acid metabolism (hsa00590)
• Reactome Pathway: Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
• BioCyc Pathway: MetaCyc:HS06681-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
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[3]
Pancreatic cancer	DISJC981	Strong	Biomarker	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[2]

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 Prostaglandin reductase 2 (PTGR2).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Prostaglandin reductase 2 (PTGR2).	[17]

15 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 Prostaglandin reductase 2 (PTGR2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Prostaglandin reductase 2 (PTGR2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Prostaglandin reductase 2 (PTGR2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Prostaglandin reductase 2 (PTGR2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Prostaglandin reductase 2 (PTGR2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Prostaglandin reductase 2 (PTGR2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Prostaglandin reductase 2 (PTGR2).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Prostaglandin reductase 2 (PTGR2).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Prostaglandin reductase 2 (PTGR2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Prostaglandin reductase 2 (PTGR2).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Prostaglandin reductase 2 (PTGR2).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Prostaglandin reductase 2 (PTGR2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Prostaglandin reductase 2 (PTGR2).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Prostaglandin reductase 2 (PTGR2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Prostaglandin reductase 2 (PTGR2).	[19]

References

• [1] Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.Thorax. 2019 Mar;74(3):237-246. doi: 10.1136/thoraxjnl-2018-211845. Epub 2019 Jan 19.
• [2] Inhibition of Prostaglandin Reductase 2, a Putative Oncogene Overexpressed in Human Pancreatic Adenocarcinoma, Induces Oxidative Stress-Mediated Cell Death Involving xCT and CTH Gene Expressions through 15-Keto-PGE2.PLoS One. 2016 Jan 28;11(1):e0147390. doi: 10.1371/journal.pone.0147390. eCollection 2016.
• [3] Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics.ACS Chem Biol. 2017 Oct 20;12(10):2671-2681. doi: 10.1021/acschembio.7b00581. Epub 2017 Sep 20.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.