Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3U1P20)

• DOT Name: Phenylalanine--tRNA ligase alpha subunit (FARSA)
• Synonyms: EC 6.1.1.20; CML33; Phenylalanyl-tRNA synthetase alpha subunit; PheRS
• Gene Name: FARSA
• Related Disease:
  Familial hypercholesterolemia
  Rajab interstitial lung disease with brain calcifications 2
  Schizophrenia
  Methicillin-resistant staphylococci infection
• UniProt ID: SYFA_HUMAN
• PDB ID: 3L4G
• EC Number: 6.1.1.20
• Pfam ID: PF18552 ; PF18554 ; PF18553 ; PF01409
• Sequence:
  MADGQVAELLLRRLEASDGGLDSAELAAELGMEHQAVVGAVKSLQALGEVIEAELRSTKH
  WELTAEGEEIAREGSHEARVFRSIPPEGLAQSELMRLPSGKVGFSKAMSNKWIRVDKSAA
  DGPRVFRVVDSMEDEVQRRLQLVRGGQAEKLGEKERSELRKRKLLAEVTLKTYWVSKGSA
  FSTSISKQETELSPEMISSGSWRDRPFKPYNFLAHGVLPDSGHLHPLLKVRSQFRQIFLE
  MGFTEMPTDNFIESSFWNFDALFQPQQHPARDQHDTFFLRDPAEALQLPMDYVQRVKRTH
  SQGGYGSQGYKYNWKLDEARKNLLRTHTTSASARALYRLAQKKPFTPVKYFSIDRVFRNE
  TLDATHLAEFHQIEGVVADHGLTLGHLMGVLREFFTKLGITQLRFKPAYNPYTEPSMEVF
  SYHQGLKKWVEVGNSGVFRPEMLLPMGLPENVSVIAWGLSLERPTMIKYGINNIRELVGH
  KVNLQMVYDSPLCRLDAEPRPPPTQEAA
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Cytosolic tRNA aminoacylation (R-HSA-379716)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[1]
Rajab interstitial lung disease with brain calcifications 2	DISO5GEH	Strong	Autosomal recessive	[2]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[3]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[12]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[13]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[16]

2 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 affects the methylation of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Phenylalanine--tRNA ligase alpha subunit (FARSA).	[18]

References

• [1] Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.Eur J Hum Genet. 2013 May;21(5):563-6. doi: 10.1038/ejhg.2012.207. Epub 2012 Sep 12.
• [2] FARSA mutations mimic phenylalanyl-tRNA synthetase deficiency caused by FARSB defects. Clin Genet. 2019 Nov;96(5):468-472. doi: 10.1111/cge.13614. Epub 2019 Aug 6.
• [3] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [4] Exploring the binding sites of Staphylococcus aureus phenylalanine tRNA synthetase: A homology model approach.J Mol Graph Model. 2017 May;73:36-47. doi: 10.1016/j.jmgm.2017.02.002. Epub 2017 Feb 10.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] 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.
• [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] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.