Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUV5EFT)

• DOT Name: Translation factor GUF1, mitochondrial (GUF1)
• Synonyms: EC 3.6.5.-; Elongation factor 4 homolog; EF-4; GTPase GUF1; Ribosomal back-translocase
• Gene Name: GUF1
• Related Disease:
  West syndrome
  Developmental and epileptic encephalopathy, 40
• UniProt ID: GUF1_HUMAN
• EC Number: 3.6.5.-
• Pfam ID: PF00679 ; PF00009 ; PF03144 ; PF06421
• Sequence:
  MWTLVGRGWGCARALAPRATGAALLVAPGPRSAPTLGAAPESWATDRLYSSAEFKEKLDM
  SRFPVENIRNFSIVAHVDHGKSTLADRLLELTGTIDKTKNNKQVLDKLQVERERGITVKA
  QTASLFYNCEGKQYLLNLIDTPGHVDFSYEVSRSLSACQGVLLVVDANEGIQAQTVANFF
  LAFEAQLSVIPVINKIDLKNADPERVENQIEKVFDIPSDECIKISAKLGTNVESVLQAII
  ERIPPPKVHRKNPLRALVFDSTFDQYRGVIANVALFDGVVSKGDKIVSAHTQKTYEVNEV
  GVLNPNEQPTHKLYAGQVGYLIAGMKDVTEAQIGDTLCLHKQPVEPLPGFKSAKPMVFAG
  MYPLDQSEYNNLKSAIEKLTLNDSSVTVHRDSSLALGAGWRLGFLGLLHMEVFNQRLEQE
  YNASVILTTPTVPYKAVLSSSKLIKEHREKEITIINPAQFPDKSKVTEYLEPVVLGTIIT
  PDEYTGKIMMLCEARRAVQKNMIFIDQNRVMLKYLFPLNEIVVDFYDSLKSLSSGYASFD
  YEDAGYQTAELVKMDILLNGNTVEELVTVVHKDKAHSIGKAICERLKDSLPRQLFEIAIQ
  AAIGSKIIARETVKAYRKNVLAKCYGGDITRKMKLLKRQAEGKKKLRKIGNVEVPKDAFI
  KVLKTQSSK
• Function: Promotes mitochondrial protein synthesis. May act as a fidelity factor of the translation reaction, by catalyzing a one-codon backward translocation of tRNAs on improperly translocated ribosomes. Binds to mitochondrial ribosomes in a GTP-dependent manner.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy, 40	DISI6DGB	Limited	Unknown	[2]

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 Translation factor GUF1, mitochondrial (GUF1).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Translation factor GUF1, mitochondrial (GUF1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Translation factor GUF1, mitochondrial (GUF1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Translation factor GUF1, mitochondrial (GUF1).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[13]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Translation factor GUF1, mitochondrial (GUF1).	[7]

References

• [1] West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1. Eur J Hum Genet. 2016 Jul;24(7):1001-8. doi: 10.1038/ejhg.2015.227. Epub 2015 Oct 21.
• [2] Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat Protoc. 2007;2(11):2692-703. doi: 10.1038/nprot.2007.376.
• [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] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.