Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3XNFJZ)

• DOT Name: Leukotriene C4 synthase (LTC4S)
• Synonyms: LTC4 synthase; EC 4.4.1.20; Glutathione S-transferase LTC4; EC 2.5.1.-; Leukotriene-C(4) synthase; Leukotriene-C4 synthase
• Gene Name: LTC4S
• UniProt ID: LTC4S_HUMAN
• PDB ID: 2PNO; 2UUH; 2UUI; 3B29; 3HKK; 3LEO; 3PCV; 4BPM; 4J7T; 4J7Y; 4JC7; 4JCZ; 4JRZ; 4WAB; 5HV9; 6R7D
• EC Number: 2.5.1.-; 4.4.1.20
• Pfam ID: PF01124
• Sequence:
  MKDEVALLAAVTLLGVLLQAYFSLQVISARRAFRVSPPLTTGPPEFERVYRAQVNCSEYF
  PLFLATLWVAGIFFHEGAAALCGLVYLFARLRYFQGYARSAQLRLAPLYASARALWLLVA
  LAALGLLAHFLPAALRAALLGRLRTLLPWA
• Function: Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity. Can also catalyze the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid to form maresin conjugate in tissue regeneration 1 (MCTR1), a bioactive lipid mediator that possess potent anti-inflammatory and proresolving actions.
• Tissue Specificity: Detected in lung, platelets and the myelogenous leukemia cell line KG-1 (at protein level). LTC4S activity is present in eosinophils, basophils, mast cells, certain phagocytic mononuclear cells, endothelial cells, vascular smooth muscle cells and platelets.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Synthesis of Lipoxins (LX) (R-HSA-2142700)
  Biosynthesis of maresin conjugates in tissue regeneration (MCTR) (R-HSA-9026762)
  Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR) (R-HSA-9026766)
  Synthesis of 5-eicosatetraenoic acids (R-HSA-2142688)
• BioCyc Pathway: MetaCyc:HS08566-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Leukotriene C4 synthase (LTC4S) affects the response to substance of Aspirin.	[6]
Ergotidine	DM78IME	Approved	Leukotriene C4 synthase (LTC4S) decreases the response to substance of Ergotidine.	[7]
Pranlukast	DMYHDCA	Approved	Leukotriene C4 synthase (LTC4S) affects the response to substance of Pranlukast.	[8]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LTC4	DM702WR	Investigative	Leukotriene C4 synthase (LTC4S) affects the chemical synthesis of LTC4.	[9]

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 Leukotriene C4 synthase (LTC4S).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Leukotriene C4 synthase (LTC4S).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Leukotriene C4 synthase (LTC4S).	[3]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Leukotriene C4 synthase (LTC4S).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etazolate	DMOCID7	Phase 2	Etazolate decreases the secretion of Leukotriene C4 synthase (LTC4S).	[5]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the secretion of Leukotriene C4 synthase (LTC4S).	[5]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the secretion of Leukotriene C4 synthase (LTC4S).	[5]
ROLIPRAM	DMJ03UM	Investigative	ROLIPRAM decreases the secretion of Leukotriene C4 synthase (LTC4S).	[5]

References

• [1] 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.
• [2] 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.
• [3] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [4] Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene. Eur J Hum Genet. 2003 Aug;11(8):619-22. doi: 10.1038/sj.ejhg.5201015.
• [5] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [6] Genetic and ethnic risk factors associated with drug hypersensitivity. Curr Opin Allergy Clin Immunol. 2010 Aug;10(4):280-90. doi: 10.1097/ACI.0b013e32833b1eb3.
• [7] The A-444C polymorphism in the leukotriene C4 synthase gene is associated with aspirin-induced urticaria. J Investig Allergol Clin Immunol. 2009;19(5):375-82.
• [8] Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics. 2002 Oct;12(7):565-70. doi: 10.1097/00008571-200210000-00009.
• [9] Aberrant expression of active leukotriene C(4) synthase in CD16(+) neutrophils from patients with chronic myeloid leukemia. Blood. 2000 Feb 15;95(4):1456-64.