Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0SGNE)

DOT Name Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1)
Synonyms EC 2.8.4.5; CDK5 regulatory subunit-associated protein 1-like 1; tRNA-t(6)A37 methylthiotransferase
Gene Name CDKAL1
Related Disease
Autism ( )
Bone inflammation disease ( )
Diabetic retinopathy ( )
Melanoma ( )
Narcolepsy ( )
Rheumatoid arthritis ( )
Spondyloarthropathy ( )
Alzheimer disease ( )
Ankylosing spondylitis ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Atopic dermatitis ( )
Bladder cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Cardiovascular disease ( )
Diabetic kidney disease ( )
High blood pressure ( )
Insulinoma ( )
Metabolic disorder ( )
Multiple sclerosis ( )
Obesity ( )
Pancreatic cancer ( )
Prediabetes syndrome ( )
Prostate cancer ( )
Prostate carcinoma ( )
Psoriasis ( )
Ulcerative colitis ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Advanced cancer ( )
Asthma ( )
Cutaneous melanoma ( )
Stroke ( )
Coronary heart disease ( )
Crohn disease ( )
Inflammatory bowel disease ( )
Sclerosing cholangitis ( )
UniProt ID
CDKAL_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
2.8.4.5
Pfam ID
PF04055 ; PF01938 ; PF00919
Sequence
MPSASCDTLLDDIEDIVSQEDSKPQDRHFVRKDVVPKVRRRNTQKYLQEEENSPPSDSTI
PGIQKIWIRTWGCSHNNSDGEYMAGQLAAYGYKITENASDADLWLLNSCTVKNPAEDHFR
NSIKKAQEENKKIVLAGCVPQAQPRQDYLKGLSIIGVQQIDRVVEVVEETIKGHSVRLLG
QKKDNGRRLGGARLDLPKIRKNPLIEIISINTGCLNACTYCKTKHARGNLASYPIDELVD
RAKQSFQEGVCEIWLTSEDTGAYGRDIGTNLPTLLWKLVEVIPEGAMLRLGMTNPPYILE
HLEEMAKILNHPRVYAFLHIPVQSASDSVLMEMKREYCVADFKRVVDFLKEKVPGITIAT
DIICGFPGETDQDFQETVKLVEEYKFPSLFINQFYPRPGTPAAKMEQVPAQVKKQRTKDL
SRVFHSYSPYDHKIGERQQVLVTEESFDSKFYVAHNQFYEQVLVPKNPAFMGKMVEVDIY
ESGKHFMKGQPVSDAKVYTPSISKPLAKGEVSGLTKDFRNGLGNQLSSGSHTSAASQCDS
ASSRMVLPMPRLHQDCALRMSVGLALLGLLFAFFVKVYN
Function
Catalyzes the methylthiolation of N6-threonylcarbamoyladenosine (t(6)A), leading to the formation of 2-methylthio-N6-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 in tRNAs that read codons beginning with adenine.
Tissue Specificity Expressed in pancreatic islets.
Reactome Pathway
tRNA modification in the nucleus and cytosol (R-HSA-6782315 )

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Autism DISV4V1Z Definitive Genetic Variation [1]
Bone inflammation disease DISTZXME Definitive Genetic Variation [2]
Diabetic retinopathy DISHGUJM Definitive Genetic Variation [3]
Melanoma DIS1RRCY Definitive Genetic Variation [4]
Narcolepsy DISLCNLI Definitive Genetic Variation [5]
Rheumatoid arthritis DISTSB4J Definitive Genetic Variation [2]
Spondyloarthropathy DISBPYCZ Definitive Genetic Variation [2]
Alzheimer disease DISF8S70 Strong Genetic Variation [6]
Ankylosing spondylitis DISRC6IR Strong Genetic Variation [2]
Arteriosclerosis DISK5QGC Strong Genetic Variation [7]
Atherosclerosis DISMN9J3 Strong Genetic Variation [7]
Atopic dermatitis DISTCP41 Strong Genetic Variation [8]
Bladder cancer DISUHNM0 Strong Genetic Variation [9]
Breast cancer DIS7DPX1 Strong Genetic Variation [10]
Breast carcinoma DIS2UE88 Strong Genetic Variation [11]
Cardiovascular disease DIS2IQDX Strong Genetic Variation [12]
Diabetic kidney disease DISJMWEY Strong Genetic Variation [13]
High blood pressure DISY2OHH Strong Genetic Variation [13]
Insulinoma DISIU1JS Strong Biomarker [14]
Metabolic disorder DIS71G5H Strong Biomarker [15]
Multiple sclerosis DISB2WZI Strong Genetic Variation [16]
Obesity DIS47Y1K Strong Genetic Variation [17]
Pancreatic cancer DISJC981 Strong Genetic Variation [18]
Prediabetes syndrome DISH2I53 Strong Genetic Variation [17]
Prostate cancer DISF190Y Strong Genetic Variation [7]
Prostate carcinoma DISMJPLE Strong Genetic Variation [7]
Psoriasis DIS59VMN Strong Genetic Variation [19]
Ulcerative colitis DIS8K27O Strong Genetic Variation [19]
Urinary bladder cancer DISDV4T7 Strong Genetic Variation [9]
Urinary bladder neoplasm DIS7HACE Strong Biomarker [20]
Advanced cancer DISAT1Z9 moderate Genetic Variation [21]
Asthma DISW9QNS moderate Genetic Variation [22]
Cutaneous melanoma DIS3MMH9 moderate Genetic Variation [23]
Stroke DISX6UHX moderate Genetic Variation [24]
Coronary heart disease DIS5OIP1 Limited Biomarker [25]
Crohn disease DIS2C5Q8 Limited Genetic Variation [26]
Inflammatory bowel disease DISGN23E Limited Genetic Variation [26]
Sclerosing cholangitis DIS7GZNB Limited Genetic Variation [19]
------------------------------------------------------------------------------------
⏷ Show the Full List of 38 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
9 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [27]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [28]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [29]
Quercetin DM3NC4M Approved Quercetin decreases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [30]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide decreases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [31]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol increases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [32]
Testosterone enanthate DMB6871 Approved Testosterone enanthate affects the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [33]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [34]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [35]
------------------------------------------------------------------------------------
⏷ Show the Full List of 9 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of Threonylcarbamoyladenosine tRNA methylthiotransferase (CDKAL1). [36]
------------------------------------------------------------------------------------

References

1 Individual common variants exert weak effects on the risk for autism spectrum disorders.Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.
2 Different Contributions of CDKAL1, KIF21B, and LRRK2/MUC19 Polymorphisms to SAPHO Syndrome, Rheumatoid Arthritis, Ankylosing Spondylitis, and Seronegative Spondyloarthropathy.Genet Test Mol Biomarkers. 2017 Feb;21(2):122-126. doi: 10.1089/gtmb.2016.0112. Epub 2016 Dec 12.
3 CDKAL1 rs7756992 is associated with diabetic retinopathy in a Chinese population with type 2 diabetes.Sci Rep. 2017 Aug 18;7(1):8812. doi: 10.1038/s41598-017-09010-w.
4 Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.Oncotarget. 2017 Mar 14;8(11):17586-17592. doi: 10.18632/oncotarget.15230.
5 Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
6 Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
7 Diabetes genes and prostate cancer in the Atherosclerosis Risk in Communities study.Cancer Epidemiol Biomarkers Prev. 2010 Feb;19(2):558-65. doi: 10.1158/1055-9965.EPI-09-0902.
8 Association of CDKAL1 Polymorphisms with Early-Onset Atopic Dermatitis in Koreans.Ann Dermatol. 2018 Jun;30(3):276-283. doi: 10.5021/ad.2018.30.3.276. Epub 2018 Apr 23.
9 Genome-wide association study identifies multiple loci associated with bladder cancer risk.Hum Mol Genet. 2014 Mar 1;23(5):1387-98. doi: 10.1093/hmg/ddt519. Epub 2013 Oct 24.
10 Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women.Cancer Causes Control. 2016 Aug;27(8):965-76. doi: 10.1007/s10552-016-0774-x. Epub 2016 Jun 17.
11 Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
12 Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
13 Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population.J Diabetes. 2015 Jan;7(1):102-13. doi: 10.1111/1753-0407.12147. Epub 2014 Apr 21.
14 CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1) is a tail-anchored protein in the endoplasmic reticulum (ER) of insulinoma cells.J Biol Chem. 2012 Dec 7;287(50):41808-19. doi: 10.1074/jbc.M112.376558. Epub 2012 Oct 9.
15 CDK5 Regulatory Subunit-Associated Protein 1-like 1 Negatively Regulates Adipocyte Differentiation through Activation of Wnt Signaling Pathway.Sci Rep. 2017 Aug 4;7(1):7326. doi: 10.1038/s41598-017-06469-5.
16 Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
17 Protective Effects of an Obesity-Associated Polymorphism (CDKAL1 rs9356744) on Prediabetes: The Cardiometabolic Risk in Chinese (CRC) Study.Exp Clin Endocrinol Diabetes. 2018 Sep;126(9):540-545. doi: 10.1055/s-0042-109607. Epub 2018 Jun 22.
18 Case-control study of diabetes-related genetic variants and pancreatic cancer risk in Japan.World J Gastroenterol. 2014 Dec 14;20(46):17456-62. doi: 10.3748/wjg.v20.i46.17456.
19 Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
20 Inactivation of the Rb pathway and overexpression of both isoforms of E2F3 are obligate events in bladder tumours with 6p22 amplification.Oncogene. 2008 Apr 24;27(19):2716-27. doi: 10.1038/sj.onc.1210934. Epub 2007 Nov 26.
21 Genetic variants for type 2 diabetes and new-onset cancer in Chinese with type 2 diabetes.Diabetes Res Clin Pract. 2014 Feb;103(2):328-37. doi: 10.1016/j.diabres.2013.12.016. Epub 2013 Dec 27.
22 Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.Eur J Hum Genet. 2011 Apr;19(4):458-64. doi: 10.1038/ejhg.2010.191. Epub 2010 Dec 8.
23 Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.Nat Genet. 2015 Sep;47(9):987-995. doi: 10.1038/ng.3373. Epub 2015 Aug 3.
24 Genome-wide association analysis of ischemic stroke in young adults.G3 (Bethesda). 2011 Nov;1(6):505-14. doi: 10.1534/g3.111.001164. Epub 2011 Nov 1.
25 Bayesian refinement of association signals for 14 loci in 3 common diseases.Nat Genet. 2012 Dec;44(12):1294-301. doi: 10.1038/ng.2435. Epub 2012 Oct 28.
26 Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
27 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
28 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.
29 Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
30 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.
31 Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
32 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.
33 Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
34 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.
35 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
36 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.