Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6A9JT8)

• DOT Name: Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3)
• Synonyms: EC 3.1.1.47; PAF acetylhydrolase 29 kDa subunit; PAF-AH 29 kDa subunit; PAF-AH subunit gamma; PAFAH subunit gamma
• Gene Name: PAFAH1B3
• Related Disease:
  Hypopharyngeal squamous cell carcinoma
  Intellectual disability
• UniProt ID: PA1B3_HUMAN
• EC Number: 3.1.1.47
• Pfam ID: PF13472
• Sequence:
  MSGEENPASKPTPVQDVQGDGRWMSLHHRFVADSKDKEPEVVFIGDSLVQLMHQCEIWRE
  LFSPLHALNFGIGGDGTQHVLWRLENGELEHIRPKIVVVWVGTNNHGHTAEQVTGGIKAI
  VQLVNERQPQARVVVLGLLPRGQHPNPLREKNRQVNELVRAALAGHPRAHFLDADPGFVH
  SDGTISHHDMYDYLHLSRLGYTPVCRALHSLLLRLLAQDQGQGAPLLEPAP
• Function: Alpha1 catalytic subunit of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)) heterotetrameric enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and modulates the action of PAF. The activity and substrate specificity of PAF-AH (I) are affected by its subunit composition. Both alpha1/alpha1 homodimer (PAFAH1B3/PAFAH1B3 homodimer) and alpha1/alpha2 heterodimer(PAFAH1B3/PAFAH1B2 heterodimer) hydrolyze 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoric acid (AAGPA) more efficiently than PAF, but they have little hydrolytic activity towards 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylethanolamine (AAGPE). Plays an important role during the development of brain.
• Tissue Specificity: In the adult, expressed in brain, skeletal muscle, kidney, thymus, spleen, colon, testis, ovary and peripheral blood leukocytes. In the fetus, highest expression occurs in brain.
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway: COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypopharyngeal squamous cell carcinoma	DISDDD65	Strong	Altered Expression	[1]
Intellectual disability	DISMBNXP	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3) increases the response to substance of Cisplatin.	[21]

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 Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[16]

17 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 Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha1 (PAFAH1B3).	[20]

References

• [1] Aberrant expression of PAFAH1B3 associates with poor prognosis and affects proliferation and aggressiveness in hypopharyngeal squamous cell carcinoma.Onco Targets Ther. 2019 Apr 11;12:2799-2808. doi: 10.2147/OTT.S196324. eCollection 2019.
• [2] Functional hemizygosity of PAFAH1B3 due to a PAFAH1B3-CLK2 fusion gene in a female with mental retardation, ataxia and atrophy of the brain.Hum Mol Genet. 2001 Apr 1;10(8):797-806. doi: 10.1093/hmg/10.8.797.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] 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.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] 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.
• [18] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [19] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [21] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.