Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8N9TT5)

• DOT Name: Phenylalanine--tRNA ligase beta subunit (FARSB)
• Synonyms: EC 6.1.1.20; Phenylalanyl-tRNA synthetase beta subunit; PheRS
• Gene Name: FARSB
• Related Disease:
  Intellectual disability
  Isolated congenital microcephaly
  Rajab interstitial lung disease with brain calcifications 1
  Rajab interstitial lung disease with brain calcifications
• UniProt ID: SYFB_HUMAN
• PDB ID: 3L4G
• EC Number: 6.1.1.20
• Pfam ID: PF03483 ; PF03484 ; PF18262 ; PF17759
• Sequence:
  MPTVSVKRDLLFQALGRTYTDEEFDELCFEFGLELDEITSEKEIISKEQGNVKAAGASDV
  VLYKIDVPANRYDLLCLEGLVRGLQVFKERIKAPVYKRVMPDGKIQKLIITEETAKIRPF
  AVAAVLRNIKFTKDRYDSFIELQEKLHQNICRKRALVAIGTHDLDTLSGPFTYTAKRPSD
  IKFKPLNKTKEYTACELMNIYKTDNHLKHYLHIIENKPLYPVIYDSNGVVLSMPPIINGD
  HSRITVNTRNIFIECTGTDFTKAKIVLDIIVTMFSEYCENQFTVEAAEVVFPNGKSHTFP
  ELAYRKEMVRADLINKKVGIRETPENLAKLLTRMYLKSEVIGDGNQIEIEIPPTRADIIH
  ACDIVEDAAIAYGYNNIQMTLPKTYTIANQFPLNKLTELLRHDMAAAGFTEALTFALCSQ
  EDIADKLGVDISATKAVHISNPKTAEFQVARTTLLPGLLKTIAANRKMPLPLKLFEISDI
  VIKDSNTDVGAKNYRHLCAVYYNKNPGFEIIHGLLDRIMQLLDVPPGEDKGGYVIKASEG
  PAFFPGRCAEIFARGQSVGKLGVLHPDVITKFELTMPCSSLEINVGPFL
• 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
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[1]
Rajab interstitial lung disease with brain calcifications 1	DISV7GZY	Strong	Autosomal recessive	[2]
Rajab interstitial lung disease with brain calcifications	DISP95VU	Limited	Genetic Variation	[2]

25 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 beta subunit (FARSB).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[12]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[13]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[14]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[16]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[17]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[18]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Phenylalanine--tRNA ligase beta subunit (FARSB).	[25]

References

• [1] Homozygosity for FARSB mutation leads to Phe-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease. Hum Mutat. 2018 Oct;39(10):1355-1359. doi: 10.1002/humu.23595. Epub 2018 Jul 30.
• [2] Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease. Hum Mutat. 2018 Jun;39(6):834-840. doi: 10.1002/humu.23424. Epub 2018 Apr 10.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [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] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [18] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] 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.
• [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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.