Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT71NN7C)

• DOT Name: Prostaglandin-H2 D-isomerase (PTGDS)
• Synonyms: EC 5.3.99.2; Beta-trace protein; Cerebrin-28; Glutathione-independent PGD synthase; Lipocalin-type prostaglandin-D synthase; L-PGDS; Prostaglandin-D2 synthase; PGD2 synthase; PGDS; PGDS2
• Gene Name: PTGDS
• UniProt ID: PTGDS_HUMAN
• PDB ID: 2WWP; 3O19; 3O22; 3O2Y; 4IMN; 4IMO; 4ORR; 4ORS; 4ORU; 4ORW; 4ORX; 4ORY; 4OS0; 4OS3; 4OS8; 5WY9; 8HTA
• EC Number: 5.3.99.2
• Pfam ID: PF00061
• Sequence:
  MATHHTLWMGLALLGVLGDLQAAPEAQVSVQPNFQQDKFLGRWFSAGLASNSSWLREKKA
  ALSMCKSVVAPATDGGLNLTSTFLRKNQCETRTMLLQPAGSLGSYSYRSPHWGSTYSVSV
  VETDYDQYALLYSQGSKGPGEDFRMATLYSRTQTPRAELKEKFTAFCKAQGFTEDTIVFL
  PQTDKCMTEQ
• Function: Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation. Involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophobic molecules and as a secretory retinoid and thyroid hormone transporter. Possibly involved in development and maintenance of the blood-brain, blood-retina, blood-aqueous humor and blood-testis barrier. It is likely to play important roles in both maturation and maintenance of the central nervous system and male reproductive system. Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR.
• Tissue Specificity: Abundant in the brain and CNS, where it is expressed in tissues of the blood-brain barrier and secreted into the cerebro-spinal fluid. Abundantly expressed in the heart. In the male reproductive system, it is expressed in the testis, epididymis and prostate, and is secreted into the seminal fluid. Expressed in the eye and secreted into the aqueous humor. Lower levels detected in various tissue fluids such as serum, normal urine, ascitic fluid and tear fluid. Also found in a number of other organs including ovary, fimbriae of the fallopian tubes, kidney, leukocytes.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Transcriptional regulation of testis differentiation (R-HSA-9690406)
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
• BioCyc Pathway: MetaCyc:HS02989-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Prostaglandin-H2 D-isomerase (PTGDS) affects the binding of Tretinoin.	[18]

1 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 Prostaglandin-H2 D-isomerase (PTGDS).	[1]

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 Prostaglandin-H2 D-isomerase (PTGDS).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[8]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[12]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[17]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Prostaglandin-H2 D-isomerase (PTGDS).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin A	DMJ2AH4	Approved	Vitamin A affects the binding of Prostaglandin-H2 D-isomerase (PTGDS).	[10]
Acteoside	DM0YHKB	Terminated	Acteoside affects the binding of Prostaglandin-H2 D-isomerase (PTGDS).	[14]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the secretion of Prostaglandin-H2 D-isomerase (PTGDS).	[19]
AMENTOFLAVONE	DMLRNV2	Investigative	AMENTOFLAVONE affects the binding of Prostaglandin-H2 D-isomerase (PTGDS).	[14]
1-anilinonaphthalene-8-sulfonic acid	DMNGY0E	Investigative	1-anilinonaphthalene-8-sulfonic acid affects the binding of Prostaglandin-H2 D-isomerase (PTGDS).	[10]

References

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• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] Unique signatures of stress-induced senescent human astrocytes. Exp Neurol. 2020 Dec;334:113466. doi: 10.1016/j.expneurol.2020.113466. Epub 2020 Sep 17.
• [5] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] 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.
• [9] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [10] Comparative ligand-binding analysis of ten human lipocalins. Biochim Biophys Acta. 2006 Feb;1764(2):161-73. doi: 10.1016/j.bbapap.2005.12.006. Epub 2006 Jan 6.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] 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.
• [13] Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib. J Lipid Res. 2013 Nov;54(11):3116-29.
• [14] In silico prediction of prostaglandin D2 synthase inhibitors from herbal constituents for the treatment of hair loss. J Ethnopharmacol. 2015 Dec 4;175:470-80. doi: 10.1016/j.jep.2015.10.005. Epub 2015 Oct 9.
• [15] The prostaglandin synthases, COX-2 and L-PGDS, mediate prostate hyperplasia induced by low-dose bisphenol A. Sci Rep. 2020 Aug 4;10(1):13108. doi: 10.1038/s41598-020-69809-y.
• [16] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [17] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [18] Prevention of paraquat-induced apoptosis in human neuronal SH-SY5Y cells by lipocalin-type prostaglandin D synthase. J Neurochem. 2012 Jan;120(2):279-91. doi: 10.1111/j.1471-4159.2011.07570.x. Epub 2011 Nov 24.
• [19] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.