Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXK0FLB)

• DOT Name: Bifunctional glutamate/proline--tRNA ligase (EPRS1)
• Synonyms: Bifunctional aminoacyl-tRNA synthetase; Cell proliferation-inducing gene 32 protein; Glutamatyl-prolyl-tRNA synthetase
• Gene Name: EPRS1
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Epilepsy
  Breast cancer
  Breast neoplasm
  Cardiac disease
  Chikungunya virus infection
  Coccidiosis
  Coronary atherosclerosis
  Disorder of orbital region
  Estrogen-receptor positive breast cancer
  Isolated congenital microcephaly
  Leukodystrophy, hypomyelinating, 15
  Myocardial ischemia
  Neoplasm
  Cardiovascular disease
  Coronary heart disease
  Methicillin-resistant staphylococci infection
  Myocardial infarction
  Pulmonary disease
  Parkinson disease
  Anxiety
  Anxiety disorder
  Congenital heart disease
  Proliferative vitreoretinopathy
• UniProt ID: SYEP_HUMAN
• PDB ID: 1FYJ; 4HVC; 4K86; 4K87; 4K88; 5A1N; 5A34; 5A5H; 5BMU; 5V58; 5VAD; 5Y6L; 6IY6; 7BBU; 7F98; 7F99; 7F9A; 7F9B; 7F9C; 7F9D; 7OSY; 7OSZ; 7OT0; 7OT1; 7OT2; 7OT3; 7X09; 7X1O; 7Y1H; 7Y1W; 7Y28; 7Y3S
• EC Number: 6.1.1.15; 6.1.1.17
• Pfam ID: PF03129 ; PF09180 ; PF00749 ; PF03950 ; PF20974 ; PF00587 ; PF00458
• Sequence:
  MATLSLTVNSGDPPLGALLAVEHVKDDVSISVEEGKENILHVSENVIFTDVNSILRYLAR
  VATTAGLYGSNLMEHTEIDHWLEFSATKLSSCDSFTSTINELNHCLSLRTYLVGNSLSLA
  DLCVWATLKGNAAWQEQLKQKKAPVHVKRWFGFLEAQQAFQSVGTKWDVSTTKARVAPEK
  KQDVGKFVELPGAEMGKVTVRFPPEASGYLHIGHAKAALLNQHYQVNFKGKLIMRFDDTN
  PEKEKEDFEKVILEDVAMLHIKPDQFTYTSDHFETIMKYAEKLIQEGKAYVDDTPAEQMK
  AEREQRIDSKHRKNPIEKNLQMWEEMKKGSQFGQSCCLRAKIDMSSNNGCMRDPTLYRCK
  IQPHPRTGNKYNVYPTYDFACPIVDSIEGVTHALRTTEYHDRDEQFYWIIEALGIRKPYI
  WEYSRLNLNNTVLSKRKLTWFVNEGLVDGWDDPRFPTVRGVLRRGMTVEGLKQFIAAQGS
  SRSVVNMEWDKIWAFNKKVIDPVAPRYVALLKKEVIPVNVPEAQEEMKEVAKHPKNPEVG
  LKPVWYSPKVFIEGADAETFSEGEMVTFINWGNLNITKIHKNADGKIISLDAKLNLENKD
  YKKTTKVTWLAETTHALPIPVICVTYEHLITKPVLGKDEDFKQYVNKNSKHEELMLGDPC
  LKDLKKGDIIQLQRRGFFICDQPYEPVSPYSCKEAPCVLIYIPDGHTKEMPTSGSKEKTK
  VEATKNETSAPFKERPTPSLNNNCTTSEDSLVLYNRVAVQGDVVRELKAKKAPKEDVDAA
  VKQLLSLKAEYKEKTGQEYKPGNPPAEIGQNISSNSSASILESKSLYDEVAAQGEVVRKL
  KAEKSPKAKINEAVECLLSLKAQYKEKTGKEYIPGQPPLSQSSDSSPTRNSEPAGLETPE
  AKVLFDKVASQGEVVRKLKTEKAPKDQVDIAVQELLQLKAQYKSLIGVEYKPVSATGAED
  KDKKKKEKENKSEKQNKPQKQNDGQRKDPSKNQGGGLSSSGAGEGQGPKKQTRLGLEAKK
  EENLADWYSQVITKSEMIEYHDISGCYILRPWAYAIWEAIKDFFDAEIKKLGVENCYFPM
  FVSQSALEKEKTHVADFAPEVAWVTRSGKTELAEPIAIRPTSETVMYPAYAKWVQSHRDL
  PIKLNQWCNVVRWEFKHPQPFLRTREFLWQEGHSAFATMEEAAEEVLQILDLYAQVYEEL
  LAIPVVKGRKTEKEKFAGGDYTTTIEAFISASGRAIQGGTSHHLGQNFSKMFEIVFEDPK
  IPGEKQFAYQNSWGLTTRTIGVMTMVHGDNMGLVLPPRVACVQVVIIPCGITNALSEEDK
  EALIAKCNDYRRRLLSVNIRVRADLRDNYSPGWKFNHWELKGVPIRLEVGPRDMKSCQFV
  AVRRDTGEKLTVAENEAETKLQAILEDIQVTLFTRASEDLKTHMVVANTMEDFQKILDSG
  KIVQIPFCGEIDCEDWIKKTTARDQDLEPGAPSMGAKSLCIPFKPLCELQPGAKCVCGKN
  PAKYYTLFGRSY
• Function: Multifunctional protein which primarily functions within the aminoacyl-tRNA synthetase multienzyme complex, also known as multisynthetase complex. Within the complex it catalyzes the attachment of both L-glutamate and L-proline to their cognate tRNAs in a two-step reaction where the amino acid is first activated by ATP to form a covalent intermediate with AMP. Subsequently, the activated amino acid is transferred to the acceptor end of the cognate tRNA to form L-glutamyl-tRNA(Glu) and L-prolyl-tRNA(Pro). Upon interferon-gamma stimulation, EPRS1 undergoes phosphorylation, causing its dissociation from the aminoacyl-tRNA synthetase multienzyme complex. It is recruited to form the GAIT complex, which binds to stem loop-containing GAIT elements found in the 3'-UTR of various inflammatory mRNAs, such as ceruloplasmin. The GAIT complex inhibits the translation of these mRNAs, allowing interferon-gamma to redirect the function of EPRS1 from protein synthesis to translation inhibition in specific cell contexts. Furthermore, it can function as a downstream effector in the mTORC1 signaling pathway, by promoting the translocation of SLC27A1 from the cytoplasm to the plasma membrane where it mediates the uptake of long-chain fatty acid by adipocytes. Thereby, EPRS1 also plays a role in fat metabolism and more indirectly influences lifespan.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Aminoacyl-tR. biosynthesis (hsa00970)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  Cytosolic tRNA aminoacylation (R-HSA-379716)
  tRNA modification in the nucleus and cytosol (R-HSA-6782315)
  Selenoamino acid metabolism (R-HSA-2408522)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Genetic Variation	[1]
Atherosclerosis	DISMN9J3	Definitive	Genetic Variation	[1]
Epilepsy	DISBB28L	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[4]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[5]
Coccidiosis	DISVU41B	Strong	Biomarker	[6]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[7]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[8]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[9]
Leukodystrophy, hypomyelinating, 15	DIS2LO8B	Strong	Autosomal recessive	[10]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[11]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[12]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[13]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[14]
Pulmonary disease	DIS6060I	moderate	Biomarker	[15]
Parkinson disease	DISQVHKL	Disputed	Genetic Variation	[16]
Anxiety	DISIJDBA	Limited	Biomarker	[17]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[17]
Congenital heart disease	DISQBA23	Limited	Biomarker	[18]
Proliferative vitreoretinopathy	DISZTEK1	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Bifunctional glutamate/proline--tRNA ligase (EPRS1) affects the response to substance of Methotrexate.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[23]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[27]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[25]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[28]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[29]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[23]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[23]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[23]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[23]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[32]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[34]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[36]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[37]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[38]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[39]

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 Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[31]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Bifunctional glutamate/proline--tRNA ligase (EPRS1).	[33]

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