Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT5KPUB)

• DOT Name: Transketolase (TKT)
• Synonyms: TK; EC 2.2.1.1
• Gene Name: TKT
• Related Disease: Transketolase deficiency
• UniProt ID: TKT_HUMAN
• PDB ID: 3MOS; 3OOY; 4KXU; 4KXV; 4KXW; 4KXX; 4KXY; 6HA3; 6HAD; 6RJB
• EC Number: 2.2.1.1
• Pfam ID: PF02779 ; PF02780 ; PF00456
• Sequence:
  MESYHKPDQQKLQALKDTANRLRISSIQATTAAGSGHPTSCCSAAEIMAVLFFHTMRYKS
  QDPRNPHNDRFVLSKGHAAPILYAVWAEAGFLAEAELLNLRKISSDLDGHPVPKQAFTDV
  ATGSLGQGLGAACGMAYTGKYFDKASYRVYCLLGDGELSEGSVWEAMAFASIYKLDNLVA
  ILDINRLGQSDPAPLQHQMDIYQKRCEAFGWHAIIVDGHSVEELCKAFGQAKHQPTAIIA
  KTFKGRGITGVEDKESWHGKPLPKNMAEQIIQEIYSQIQSKKKILATPPQEDAPSVDIAN
  IRMPSLPSYKVGDKIATRKAYGQALAKLGHASDRIIALDGDTKNSTFSEIFKKEHPDRFI
  ECYIAEQNMVSIAVGCATRNRTVPFCSTFAAFFTRAFDQIRMAAISESNINLCGSHCGVS
  IGEDGPSQMALEDLAMFRSVPTSTVFYPSDGVATEKAVELAANTKGICFIRTSRPENAII
  YNNNEDFQVGQAKVVLKSKDDQVTVIGAGVTLHEALAAAELLKKEKINIRVLDPFTIKPL
  DRKLILDSARATKGRILTVEDHYYEGGIGEAVSSAVVGEPGITVTHLAVNRVPRSGKPAE
  LLKMFGIDRDAIAQAVRGLITKA
• Function: Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate.
• KEGG Pathway:
  Pentose phosphate pathway (hsa00030)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway:
  Pentose phosphate pathway (R-HSA-71336)
  NFE2L2 regulates pentose phosphate pathway genes (R-HSA-9818028)
  Insulin effects increased synthesis of Xylulose-5-Phosphate (R-HSA-163754)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Transketolase deficiency	DISDJL64	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitrofurazone	DMSM2KE	Approved	Transketolase (TKT) increases the Vitamin B complex deficiency ADR of Nitrofurazone.	[25]
Tolazamide	DMIHRNA	Approved	Transketolase (TKT) increases the Encephalopathy ADR of Tolazamide.	[25]

20 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 Transketolase (TKT).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transketolase (TKT).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transketolase (TKT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transketolase (TKT).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Transketolase (TKT).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin affects the expression of Transketolase (TKT).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Transketolase (TKT).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Transketolase (TKT).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transketolase (TKT).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Transketolase (TKT).	[11]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Transketolase (TKT).	[12]
Cocaine	DMSOX7I	Approved	Cocaine affects the expression of Transketolase (TKT).	[13]
Clavulanate	DM2FGRT	Approved	Clavulanate increases the expression of Transketolase (TKT).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Transketolase (TKT).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Transketolase (TKT).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transketolase (TKT).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transketolase (TKT).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Transketolase (TKT).	[22]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Transketolase (TKT).	[23]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Transketolase (TKT).	[24]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB increases the metabolism of Transketolase (TKT).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transketolase (TKT).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Transketolase (TKT).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transketolase (TKT).	[20]

References

• [1] Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects. Am J Hum Genet. 2016 Jun 2;98(6):1235-1242. doi: 10.1016/j.ajhg.2016.03.030.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics. Toxicol Appl Pharmacol. 2010 Jan 15;242(2):126-35. doi: 10.1016/j.taap.2009.09.016. Epub 2009 Oct 7.
• [9] 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.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [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] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [13] Proteomic analysis of the nucleus accumbens of rats with different vulnerability to cocaine addiction. Neuropharmacology. 2009 Jul;57(1):41-8. doi: 10.1016/j.neuropharm.2009.04.005. Epub 2009 Apr 22.
• [14] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [15] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [16] Determination of Protein Haptenation by Chemical Sensitizers Within the Complexity of the Human Skin Proteome. Toxicol Sci. 2018 Apr 1;162(2):429-438. doi: 10.1093/toxsci/kfx265.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [25] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.