Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXAK6F0)

• DOT Name: Phenylalanine--tRNA ligase, mitochondrial (FARS2)
• Synonyms: EC 6.1.1.20; Phenylalanyl-tRNA synthetase; PheRS
• Gene Name: FARS2
• Related Disease:
  Combined oxidative phosphorylation defect type 14
  Hereditary spastic paraplegia 77
  Leigh syndrome
• UniProt ID: SYFM_HUMAN
• PDB ID: 3CMQ; 3HFV; 3TEG; 3TUP; 5MGH; 5MGU; 5MGV; 5MGW; 8P8X
• EC Number: 6.1.1.20
• Pfam ID: PF03147 ; PF01409
• Sequence:
  MVGSALRRGAHAYVYLVSKASHISRGHQHQAWGSRPPAAECATQRAPGSVVELLGKSYPQ
  DDHSNLTRKVLTRVGRNLHNQQHHPLWLIKERVKEHFYKQYVGRFGTPLFSVYDNLSPVV
  TTWQNFDSLLIPADHPSRKKGDNYYLNRTHMLRAHTSAHQWDLLHAGLDAFLVVGDVYRR
  DQIDSQHYPIFHQLEAVRLFSKHELFAGIKDGESLQLFEQSSRSAHKQETHTMEAVKLVE
  FDLKQTLTRLMAHLFGDELEIRWVDCYFPFTHPSFEMEINFHGEWLEVLGCGVMEQQLVN
  SAGAQDRIGWAFGLGLERLAMILYDIPDIRLFWCEDERFLKQFCVSNINQKVKFQPLSKY
  PAVINDISFWLPSENYAENDFYDLVRTIGGDLVEKVDLIDKFVHPKTHKTSHCYRITYRH
  MERTLSQREVRHIHQALQEAAVQLLGVEGRF
• Function: Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation. To a lesser extent, also catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe), thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.
• KEGG Pathway: Aminoacyl-tR. biosynthesis (hsa00970)
• Reactome Pathway: Mitochondrial tRNA aminoacylation (R-HSA-379726)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined oxidative phosphorylation defect type 14	DIS775XU	Strong	Autosomal recessive	[1]
Hereditary spastic paraplegia 77	DIS4WP0I	Strong	Autosomal recessive	[2]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[3]

1 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 Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[9]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[10]
Teriflunomide	DMQ2FKJ	Approved	Teriflunomide decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phenylalanine--tRNA ligase, mitochondrial (FARS2).	[15]

References

• [1] Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. J Med Genet. 2012 Apr;49(4):234-41. doi: 10.1136/jmedgenet-2012-100836.
• [2] A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia. Hum Mutat. 2016 Feb;37(2):165-9. doi: 10.1002/humu.22930. Epub 2015 Dec 10.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells. Anticancer Res. 2005 Sep-Oct;25(5):3271-8.
• [10] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [11] Mitochondrial dysfunction induced by leflunomide and its active metabolite. Toxicology. 2018 Mar 1;396-397:33-45.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.