Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAXZJJ4)

• DOT Name: Thromboxane-A synthase (TBXAS1)
• Synonyms: TXA synthase; TXS; EC 5.3.99.5; Cytochrome P450 5A1; Hydroperoxy icosatetraenoate dehydratase; EC 4.2.1.152
• Gene Name: TBXAS1
• Related Disease: Ghosal hematodiaphyseal dysplasia
• UniProt ID: THAS_HUMAN
• EC Number: 4.2.1.152; 5.3.99.5
• Pfam ID: PF00067
• Sequence:
  MEALGFLKLEVNGPMVTVALSVALLALLKWYSTSAFSRLEKLGLRHPKPSPFIGNLTFFR
  QGFWESQMELRKLYGPLCGYYLGRRMFIVISEPDMIKQVLVENFSNFTNRMASGLEFKSV
  ADSVLFLRDKRWEEVRGALMSAFSPEKLNEMVPLISQACDLLLAHLKRYAESGDAFDIQR
  CYCNYTTDVVASVAFGTPVDSWQAPEDPFVKHCKRFFEFCIPRPILVLLLSFPSIMVPLA
  RILPNKNRDELNGFFNKLIRNVIALRDQQAAEERRRDFLQMVLDARHSASPMGVQDFDIV
  RDVFSSTGCKPNPSRQHQPSPMARPLTVDEIVGQAFIFLIAGYEIITNTLSFATYLLATN
  PDCQEKLLREVDVFKEKHMAPEFCSLEEGLPYLDMVIAETLRMYPPAFRFTREAAQDCEV
  LGQRIPAGAVLEMAVGALHHDPEHWPSPETFNPERFTAEARQQHRPFTYLPFGAGPRSCL
  GVRLGLLEVKLTLLHVLHKFRFQACPETQVPLQLESKSALGPKNGVYIKIVSR
• Function: Catalyzes the conversion of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation. Cleaves also PGH2 to 12-hydroxy-heptadecatrienoicacid (12-HHT) and malondialdehyde, which is known to act as a mediator of DNA damage. 12-HHT and malondialdehyde are formed stoichiometrically in the same amounts as TXA2. Additionally, displays dehydratase activity, toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) producing 15-KETE and 15-HETE.
• Tissue Specificity: Platelets, lung, kidney, spleen, macrophages and lung fibroblasts.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Platelet activation (hsa04611)
• Reactome Pathway:
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
  Defective TBXAS1 causes GHDD (R-HSA-5579032)
  Eicosanoids (R-HSA-211979)
• BioCyc Pathway: MetaCyc:HS00728-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
Ghosal hematodiaphyseal dysplasia	DISBFA9N	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Thromboxane-A synthase (TBXAS1) affects the response to substance of Aspirin.	[15]

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 Thromboxane-A synthase (TBXAS1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Thromboxane-A synthase (TBXAS1).	[12]

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 Thromboxane-A synthase (TBXAS1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Thromboxane-A synthase (TBXAS1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Thromboxane-A synthase (TBXAS1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Thromboxane-A synthase (TBXAS1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Thromboxane-A synthase (TBXAS1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Thromboxane-A synthase (TBXAS1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Thromboxane-A synthase (TBXAS1).	[8]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Thromboxane-A synthase (TBXAS1).	[3]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Thromboxane-A synthase (TBXAS1).	[3]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of Thromboxane-A synthase (TBXAS1).	[3]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine decreases the activity of Thromboxane-A synthase (TBXAS1).	[9]
Quinolones	DM5GVHU	Approved	Quinolones decreases the activity of Thromboxane-A synthase (TBXAS1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Thromboxane-A synthase (TBXAS1).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Thromboxane-A synthase (TBXAS1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Thromboxane-A synthase (TBXAS1).	[14]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [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] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Effects of sulfasalazine and a sulfasalazine analogue on the formation of lipoxygenase and cyclooxygenase products. Eur J Pharmacol. 1989 Oct 10;169(2-3):225-34. doi: 10.1016/0014-2999(89)90019-8.
• [10] 3,4-Dihydroquinolin-2(1H)-ones as combined inhibitors of thromboxane A2 synthase and cAMP phosphodiesterase. J Med Chem. 1992 Feb 21;35(4):620-8.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [15] Association analysis of thromboxane A synthase 1 gene polymorphisms with aspirin intolerance in asthmatic patients. Pharmacogenomics. 2011 Mar;12(3):351-63. doi: 10.2217/pgs.10.181.