Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPP3M35)

• DOT Name: Transketolase-like protein 1 (TKTL1)
• Synonyms: EC 2.2.1.1; Transketolase 2; TK 2; Transketolase-related protein
• Gene Name: TKTL1
• UniProt ID: TKTL1_HUMAN
• EC Number: 2.2.1.1
• Pfam ID: PF02779 ; PF02780 ; PF00456
• Sequence:
  MADAEARAEFPEEARPDRGTLQVLQDMASRLRIHSIRATCSTSSGHPTSCSSSSEIMSVL
  FFYIMRYKQSDPENPDNDRFVLAKRLSFVDVATGWLGQGLGVACGMAYTGKYFDRASYRV
  FCLMSDGESSEGSVWEAMAFASYYSLDNLVAIFDVNRLGHSGALPAEHCINIYQRRCEAF
  GWNTYVVDGRDVEALCQVFWQASQVKHKPTAVVAKTFKGRGTPSIEDAESWHAKPMPRER
  ADAIIKLIESQIQTSRNLDPQPPIEDSPEVNITDVRMTSPPDYRVGDKIATRKACGLALA
  KLGYANNRVVVLDGDTRYSTFSEIFNKEYPERFIECFMAEQNMVSVALGCASRGRTIAFA
  STFAAFLTRAFDHIRIGGLAESNINIIGSHCGVSVGDDGASQMALEDIAMFRTIPKCTIF
  YPTDAVSTEHAVALAANAKGMCFIRTTRPETMVIYTPQERFEIGQAKVLRHCVSDKVTVI
  GAGITVYEALAAADELSKQDIFIRVIDLFTIKPLDVATIVSSAKATEGRIITVEDHYPQG
  GIGEAVCAAVSMDPDIQVHSLAVSGVPQSGKSEELLDMYGISARHIIVAVKCMLLN
• 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; [Isoform 4]: During fetal neocortex development, may be essential to maintain the full number of basal radial glia (bRG). bRG are neural progenitor cells that undergo asymmetric divisions, generating a bRG (self-renewal) and a neuron, in contrast to basal intermediate progenitors (bIPs), which typically divide once to give rise to 2 neurons. bRG generate more cortical neurons over time than bIPs.
• Tissue Specificity: Widely expressed . Expressed in endothelial cells and in peripheral neurons (at protein level) .; [Isoform 3]: Not expressed in fetal neocortex.; [Isoform 4]: Expressed in fetal neocortex.
• KEGG Pathway:
  Pentose phosphate pathway (hsa00030)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transketolase-like protein 1 (TKTL1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transketolase-like protein 1 (TKTL1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transketolase-like protein 1 (TKTL1).	[2]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transketolase-like protein 1 (TKTL1).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Transketolase-like protein 1 (TKTL1).	[4]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Transketolase-like protein 1 (TKTL1).	[5]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Transketolase-like protein 1 (TKTL1).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transketolase-like protein 1 (TKTL1).	[8]

References

• [1] 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.
• [2] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies. PLoS Med. 2006 Dec;3(12):e486. doi: 10.1371/journal.pmed.0030486.
• [5] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [6] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [7] 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.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.