Details of Drug Off-Target (DOT)

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

• DOT Name: Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL)
• Gene Name: ASMTL
• Related Disease:
  Acute myelogenous leukaemia
  Carney complex
• UniProt ID: ASML_HUMAN
• PDB ID: 2P5X; 6XI4; 6XI5
• EC Number: 2.1.1.-; 3.6.1.9
• Pfam ID: PF16864 ; PF02545 ; PF00891
• Sequence:
  MVLCPVIGKLLHKRVVLASASPRRQEILSNAGLRFEVVPSKFKEKLDKASFATPYGYAME
  TAKQKALEVANRLYQKDLRAPDVVIGADTIVTVGGLILEKPVDKQDAYRMLSRLSGREHS
  VFTGVAIVHCSSKDHQLDTRVSEFYEETKVKFSELSEELLWEYVHSGEPMDKAGGYGIQA
  LGGMLVESVHGDFLNVVGFPLNHFCKQLVKLYYPPRPEDLRRSVKHDSIPAADTFEDLSD
  VEGGGSEPTQRDAGSRDEKAEAGEAGQATAEAECHRTRETLPPFPTRLLELIEGFMLSKG
  LLTACKLKVFDLLKDEAPQKAADIASKVDASACGMERLLDICAAMGLLEKTEQGYSNTET
  ANVYLASDGEYSLHGFIMHNNDLTWNLFTYLEFAIREGTNQHHRALGKKAEDLFQDAYYQ
  SPETRLRFMRAMHGMTKLTACQVATAFNLSRFSSACDVGGCTGALARELAREYPRMQVTV
  FDLPDIIELAAHFQPPGPQAVQIHFAAGDFFRDPLPSAELYVLCRILHDWPDDKVHKLLS
  RVAESCKPGAGLLLVETLLDEEKRVAQRALMQSLNMLVQTEGKERSLGEYQCLLELHGFH
  QVQVVHLGGVLDAILATKVAP
• Function: Nucleoside triphosphate pyrophosphatase that hydrolyzes dTTP and UTP. Can also hydrolyze CTP and the modified nucleotides pseudo-UTP, 5-methyl-UTP (m(5)UTP) and 5-methyl-CTP (m(5)CTP). Has weak activity with dCTP, 8-oxo-GTP and N(4)-methyl-dCTP. May have a dual role in cell division arrest and in preventing the incorporation of modified nucleotides into cellular nucleic acids. In addition, the presence of the putative catalytic domain of S-adenosyl-L-methionine binding in the C-terminal region argues for a methyltransferase activity (Probable).
• Tissue Specificity: Widely expressed. In adult, highly expressed in pancreas, placenta, fibroblast, thymus, prostate, testis, ovary and colon. Expressed at lower levels in spleen, small intestine and leukocytes. In fetus, expressed at high levels in the lung and kidney and at lower level in brain and liver.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Carney complex	DISVL3IP	Strong	Biomarker	[2]

16 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 Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[10]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Probable bifunctional dTTP/UTP pyrophosphatase/methyltransferase protein (ASMTL).	[15]

References

• [1] Discovery of epigenetically silenced genes in acute myeloid leukemias.Leukemia. 2007 May;21(5):1026-34. doi: 10.1038/sj.leu.2404611. Epub 2007 Mar 1.
• [2] Malignant melanotic schwannian tumor: a clinicopathologic, immunohistochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of "melanotic schwannoma".Am J Surg Pathol. 2014 Jan;38(1):94-105. doi: 10.1097/PAS.0b013e3182a0a150.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] 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.
• [9] 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.
• [10] Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study. J Nutr Sci. 2016 Apr 26;5:e17. doi: 10.1017/jns.2016.8. eCollection 2016.
• [11] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] 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.
• [16] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.