Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT3RW6N)

• DOT Name: Prostacyclin synthase (PTGIS)
• Synonyms: EC 5.3.99.4; Hydroperoxy icosatetraenoate dehydratase; EC 4.2.1.152; Prostaglandin I2 synthase
• Gene Name: PTGIS
• Related Disease: Essential hypertension, genetic
• UniProt ID: PTGIS_HUMAN
• PDB ID: 2IAG; 3B6H
• EC Number: 4.2.1.152; 5.3.99.4
• Pfam ID: PF00067
• Sequence:
  MAWAALLGLLAALLLLLLLSRRRTRRPGEPPLDLGSIPWLGYALDFGKDAASFLTRMKEK
  HGDIFTILVGGRYVTVLLDPHSYDAVVWEPRTRLDFHAYAIFLMERIFDVQLPHYSPSDE
  KARMKLTLLHRELQALTEAMYTNLHAVLLGDATEAGSGWHEMGLLDFSYSFLLRAGYLTL
  YGIEALPRTHESQAQDRVHSADVFHTFRQLDRLLPKLARGSLSVGDKDHMCSVKSRLWKL
  LSPARLARRAHRSKWLESYLLHLEEMGVSEEMQARALVLQLWATQGNMGPAAFWLLLFLL
  KNPEALAAVRGELESILWQAEQPVSQTTTLPQKVLDSTPVLDSVLSESLRLTAAPFITRE
  VVVDLAMPMADGREFNLRRGDRLLLFPFLSPQRDPEIYTDPEVFKYNRFLNPDGSEKKDF
  YKDGKRLKNYNMPWGAGHNHCLGRSYAVNSIKQFVFLVLVHLDLELINADVEIPEFDLSR
  YGFGLMQPEHDVPVRYRIRP
• Function: Catalyzes the biosynthesis and metabolism of eicosanoids. Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2), a potent mediator of vasodilation and inhibitor of platelet aggregation. Additionally, displays dehydratase activity, toward hydroperoxyeicosatetraenoates (HPETEs), especially toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE).
• Tissue Specificity: Widely expressed; particularly abundant in ovary, heart, skeletal muscle, lung and prostate.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 24-hydroxycholesterol (R-HSA-193775)
  Synthesis of bile acids and bile salts via 27-hydroxycholesterol (R-HSA-193807)
  Nicotinamide salvaging (R-HSA-197264)
  Eicosanoids (R-HSA-211979)
  Sterols are 12-hydroxylated by CYP8B1 (R-HSA-211994)
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
• BioCyc Pathway: MetaCyc:HS04738-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Essential hypertension, genetic	DISIVD4P	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
NAFAZATROM	DM31CV2	Terminated	Prostacyclin synthase (PTGIS) increases the Adverse drug reaction ADR of NAFAZATROM.	[13]

2 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 Prostacyclin synthase (PTGIS).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Prostacyclin synthase (PTGIS).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Prostacyclin synthase (PTGIS).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Prostacyclin synthase (PTGIS).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Prostacyclin synthase (PTGIS).	[5]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Prostacyclin synthase (PTGIS).	[6]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Prostacyclin synthase (PTGIS).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Prostacyclin synthase (PTGIS).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Prostacyclin synthase (PTGIS).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prostacyclin synthase (PTGIS).	[11]
acrolein	DMAMCSR	Investigative	acrolein decreases the expression of Prostacyclin synthase (PTGIS).	[12]

References

• [1] Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension. Biochem Biophys Res Commun. 2002 Oct 11;297(5):1135-9. doi: 10.1016/s0006-291x(02)02341-0.
• [2] 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.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [7] Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation. Pain. 2007 Jun;129(3):279-86.
• [8] 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.
• [9] 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.
• [10] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [12] Prostacyclin prevents pulmonary endothelial cell apoptosis induced by cigarette smoke. Am J Respir Crit Care Med. 2007 Apr 1;175(7):676-85.
• [13] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.