Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU8FWHU)

• DOT Name: Hematopoietic prostaglandin D synthase (HPGDS)
• Synonyms: H-PGDS; EC 5.3.99.2; GST class-sigma; Glutathione S-transferase; EC 2.5.1.18; Glutathione-dependent PGD synthase; Glutathione-requiring prostaglandin D synthase; Prostaglandin-H2 D-isomerase
• Gene Name: HPGDS
• UniProt ID: HPGDS_HUMAN
• PDB ID: 1IYH; 1IYI; 1V40; 2CVD; 2VCQ; 2VCW; 2VCX; 2VCZ; 2VD0; 2VD1; 3EE2; 3KXO; 3VI5; 3VI7; 4EC0; 4EDY; 4EDZ; 4EE0; 5AIS; 5AIV; 5AIX; 5YWE; 5YWX; 5YX1; 6N4E; 6W58; 6W8H; 6ZTC; 7JR6; 7JR8
• EC Number: 2.5.1.18; 5.3.99.2
• Pfam ID: PF14497 ; PF02798
• Sequence:
  MPNYKLTYFNMRGRAEIIRYIFAYLDIQYEDHRIEQADWPEIKSTLPFGKIPILEVDGLT
  LHQSLAIARYLTKNTDLAGNTEMEQCHVDAIVDTLDDFMSCFPWAEKKQDVKEQMFNELL
  TYNAPHLMQDLDTYLGGREWLIGNSVTWADFYWEICSTTLLVFKPDLLDNHPRLVTLRKK
  VQAIPAVANWIKRRPQTKL
• Function: Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.
• Tissue Specificity: Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver.
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Arachidonic acid metabolism (hsa00590)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Drug metabolism - cytochrome P450 (hsa00982)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis - D. adducts (hsa05204)
• Reactome Pathway:
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
  Glutathione conjugation (R-HSA-156590)
• BioCyc Pathway: MetaCyc:HS08788-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Hematopoietic prostaglandin D synthase (HPGDS).	[1]
Sanguinarine	DMDINFS	Approved	Sanguinarine decreases the activity of Hematopoietic prostaglandin D synthase (HPGDS).	[2]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Hematopoietic prostaglandin D synthase (HPGDS).	[5]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Hematopoietic prostaglandin D synthase (HPGDS).	[7]
Suramin	DMTOUY9	Investigative	Suramin decreases the activity of Hematopoietic prostaglandin D synthase (HPGDS).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Hematopoietic prostaglandin D synthase (HPGDS).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Hematopoietic prostaglandin D synthase (HPGDS).	[4]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Hematopoietic prostaglandin D synthase (HPGDS).	[6]

References

• [1] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [2] Identification of new inhibitors for human hematopoietic prostaglandin D2 synthase among FDA-approved drugs and other compounds. Chem Biol Interact. 2015 Mar 5;229:91-9. doi: 10.1016/j.cbi.2015.01.014. Epub 2015 Jan 17.
• [3] 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.
• [4] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [5] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [6] 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.
• [7] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.