Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCHPUD0)

• DOT Name: Thiamin pyrophosphokinase 1 (TPK1)
• Synonyms: hTPK1; EC 2.7.6.2; Placental protein 20; PP20; Thiamine pyrophosphokinase 1
• Gene Name: TPK1
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Biotin-responsive basal ganglia disease
  Breast cancer
  Breast carcinoma
  Childhood encephalopathy due to thiamine pyrophosphokinase deficiency
  Leigh syndrome
  Dystonia
  Isolated congenital microcephaly
  Nervous system disease
• UniProt ID: TPK1_HUMAN
• PDB ID: 3S4Y
• EC Number: 2.7.6.2
• Pfam ID: PF04265 ; PF04263
• Sequence:
  MEHAFTPLEPLLSTGNLKYCLVILNQPLDNYFRHLWNKALLRACADGGANRLYDITEGER
  ESFLPEFINGDFDSIRPEVREYYATKGCELISTPDQDHTDFTKCLKMLQKKIEEKDLKVD
  VIVTLGGLAGRFDQIMASVNTLFQATHITPFPIIIIQEESLIYLLQPGKHRLHVDTGMEG
  DWCGLIPVGQPCMQVTTTGLKWNLTNDVLAFGTLVSTSNTYDGSGVVTVETDHPLLWTMA
  IKS
• Function: Catalyzes the phosphorylation of thiamine to thiamine pyrophosphate. Can also catalyze the phosphorylation of pyrithiamine to pyrithiamine pyrophosphate.
• Tissue Specificity: Detected in heart, kidney, testis, small intestine and peripheral blood leukocytes, and at very low levels in a variety of tissues.
• KEGG Pathway:
  Thiamine metabolism (hsa00730)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Vitamin B1 (thiamin) metabolism (R-HSA-196819)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Biotin-responsive basal ganglia disease	DISKPI9G	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	DIS92ANW	Strong	Autosomal recessive	[5]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[6]
Dystonia	DISJLFGW	Limited	Biomarker	[7]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[8]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Thiamin pyrophosphokinase 1 (TPK1) affects the response to substance of Topotecan.	[20]

9 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 Thiamin pyrophosphokinase 1 (TPK1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[16]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Thiamin pyrophosphokinase 1 (TPK1).	[19]

4 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 Thiamin pyrophosphokinase 1 (TPK1).	[13]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Thiamin pyrophosphokinase 1 (TPK1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Thiamin pyrophosphokinase 1 (TPK1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Thiamin pyrophosphokinase 1 (TPK1).	[15]

References

• [1] The adaptive regulation of thiamine pyrophosphokinase-1 facilitates malignant growth during supplemental thiamine conditions.Oncotarget. 2018 Oct 23;9(83):35422-35438. doi: 10.18632/oncotarget.26259. eCollection 2018 Oct 23.
• [2] Estrogen receptor 1 PvuII and XbaI polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis.Genet Mol Res. 2015 Aug 10;14(3):9361-9. doi: 10.4238/2015.August.10.17.
• [3] Thiamine phosphokinase deficiency and mutation in TPK1 presenting as biotin responsive basal ganglia disease.Clin Chim Acta. 2019 Dec;499:13-15. doi: 10.1016/j.cca.2019.07.034. Epub 2019 Aug 9.
• [4] Reduction in breast cancer susceptibility due to XbaI gene polymorphism of alpha estrogen receptor gene in Jordanians.Breast Cancer (Dove Med Press). 2017 Jan 24;9:45-49. doi: 10.2147/BCTT.S125652. eCollection 2017.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] TPK1 mutation induced childhood onset idiopathic generalized dystonia: Report of a rare mutation and effect of deep brain stimulation.J Neurol Sci. 2017 May 15;376:42-43. doi: 10.1016/j.jns.2017.02.063. Epub 2017 Mar 1.
• [8] Thiamine metabolism is critical for regulating correlated growth of dendrite arbors and neuronal somata.Sci Rep. 2017 Jul 13;7(1):5342. doi: 10.1038/s41598-017-05476-w.
• [9] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [17] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.