Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDEJXD0)

• DOT Name: Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1)
• Synonyms: EC 2.8.4.3; CDK5 activator-binding protein C42; CDK5 regulatory subunit-associated protein 1; mt-tRNA-2-methylthio-N6-dimethylallyladenosine synthase; mt-tRNA-N6-(dimethylallyl)adenosine(37) methylthiotransferase
• Gene Name: CDK5RAP1
• Related Disease:
  Advanced cancer
  B-cell neoplasm
  Melanoma
  Myopathy
  Neuralgia
  Vitiligo
• UniProt ID: CK5P1_HUMAN
• EC Number: 2.8.4.3
• Pfam ID: PF04055 ; PF01938 ; PF00919
• Sequence:
  MHPLQCVLQVQRSLGWGPLASVSWLSLRMCRAHSSLSSTMCPSPERQEDGARKDFSSRLA
  AGPTFQHFLKSASAPQEKLSSEVEDPPPYLMMDELLGRQRKVYLETYGCQMNVNDTEIAW
  SILQKSGYLRTSNLQEADVILLVTCSIREKAEQTIWNRLHQLKALKTRRPRSRVPLRIGI
  LGCMAERLKEEILNREKMVDILAGPDAYRDLPRLLAVAESGQQAANVLLSLDETYADVMP
  VQTSASATSAFVSIMRGCDNMCSYCIVPFTRGRERSRPIASILEEVKKLSEQVFLPPRPP
  KVLGLQGLKEVTLLGQNVNSFRDNSEVQFNSAVPTNLSRGFTTNYKTKQGGLRFAHLLDQ
  VSRVDPEMRIRFTSPHPKDFPDEVLQLIHERDNICKQIHLPAQSGSSRVLEAMRRGYSRE
  AYVELVHHIRESIPGVSLSSDFIAGFCGETEEDHVQTVSLLREVQYNMGFLFAYSMRQKT
  RAYHRLKDDVPEEVKLRRLEELITIFREEATKANQTSVGCTQLVLVEGLSKRSATDLCGR
  NDGNLKVIFPDAEMEDVNNPGLRVRAQPGDYVLVKITSASSQTLRGHVLCRTTLRDSSAY
  C
• Function: Methylthiotransferase that catalyzes the conversion of N6-(dimethylallyl)adenosine (i(6)A) to 2-methylthio-N6-(dimethylallyl)adenosine (ms(2)i(6)A) at position 37 (adjacent to the 3'-end of the anticodon) of four mitochondrial DNA-encoded tRNAs (Ser(UCN), Phe, Tyr and Trp). Essential for efficient and highly accurate protein translation by the ribosome. Specifically inhibits CDK5 activation by CDK5R1. Essential for efficient mitochondrial protein synthesis and respiratory chain; shows pathological consequences in mitochondrial disease.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas . Expressed in neurons of central nervous tissue .; [Isoform 5]: Mainly expressed in brain, placenta and testis.; [Isoform 6]: High expression in placenta and lung.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
B-cell neoplasm	DISVY326	Definitive	Altered Expression	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Myopathy	DISOWG27	Strong	Biomarker	[2]
Neuralgia	DISWO58J	Strong	Biomarker	[3]
Vitiligo	DISR05SL	Strong	Biomarker	[4]

6 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 Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Mitochondrial tRNA methylthiotransferase CDK5RAP1 (CDK5RAP1).	[13]

References

• [1] CDK5RAP1 targeting NF-B signaling pathway in human malignant melanoma A375 cell apoptosis.Oncol Lett. 2018 Apr;15(4):4767-4774. doi: 10.3892/ol.2018.7920. Epub 2018 Feb 1.
• [2] Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans.Cell Metab. 2015 Mar 3;21(3):428-42. doi: 10.1016/j.cmet.2015.01.019.
• [3] PiRNA-DQ541777 Contributes to Neuropathic Pain via Targeting Cdk5rap1.J Neurosci. 2019 Nov 6;39(45):9028-9039. doi: 10.1523/JNEUROSCI.1602-19.2019. Epub 2019 Sep 13.
• [4] Association between CDK5RAP1 polymorphisms and susceptibility to vitiligo in the Korean population.Eur J Dermatol. 2012 Jul-Aug;22(4):495-9. doi: 10.1684/ejd.2012.1728.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] 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.
• [13] 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.