Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8XE052)

• DOT Name: Bifunctional purine biosynthesis protein ATIC (ATIC)
• Synonyms: AICAR transformylase/inosine monophosphate cyclohydrolase; ATIC
• Gene Name: ATIC
• Related Disease: AICA-ribosiduria
• UniProt ID: PUR9_HUMAN
• PDB ID: 1P4R; 1PKX; 1PL0; 5UY8; 5UZ0
• EC Number: 2.1.2.3; 3.5.4.10
• Pfam ID: PF01808 ; PF02142
• Sequence:
  MAPGQLALFSVSDKTGLVEFARNLTALGLNLVASGGTAKALRDAGLAVRDVSELTGFPEM
  LGGRVKTLHPAVHAGILARNIPEDNADMARLDFNLIRVVACNLYPFVKTVASPGVTVEEA
  VEQIDIGGVTLLRAAAKNHARVTVVCEPEDYVVVSTEMQSSESKDTSLETRRQLALKAFT
  HTAQYDEAISDYFRKQYSKGVSQMPLRYGMNPHQTPAQLYTLQPKLPITVLNGAPGFINL
  CDALNAWQLVKELKEALGIPAAASFKHVSPAGAAVGIPLSEDEAKVCMVYDLYKTLTPIS
  AAYARARGADRMSSFGDFVALSDVCDVPTAKIISREVSDGIIAPGYEEEALTILSKKKNG
  NYCVLQMDQSYKPDENEVRTLFGLHLSQKRNNGVVDKSLFSNVVTKNKDLPESALRDLIV
  ATIAVKYTQSNSVCYAKNGQVIGIGAGQQSRIHCTRLAGDKANYWWLRHHPQVLSMKFKT
  GVKRAEISNAIDQYVTGTIGEDEDLIKWKALFEEVPELLTEAEKKEWVEKLTEVSISSDA
  FFPFRDNVDRAKRSGVAYIAAPSGSAADKVVIEACDELGIILAHTNLRLFHH
• Function: Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis. Acts as a transformylase that incorporates a formyl group to the AMP analog AICAR (5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide) to produce the intermediate formyl-AICAR (FAICAR). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction. Also catalyzes the cyclization of FAICAR to IMP. Is able to convert thio-AICAR to 6-mercaptopurine ribonucleotide, an inhibitor of purine biosynthesis used in the treatment of human leukemias. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization.
• Tissue Specificity: Present in the heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
  Antifolate resistance (hsa01523)
• Reactome Pathway:
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Purine ribonucleoside monophosphate biosynthesis (R-HSA-73817)
• BioCyc Pathway: MetaCyc:HS06490-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
AICA-ribosiduria	DISERYCZ	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[17]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Bifunctional purine biosynthesis protein ATIC (ATIC).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Bifunctional purine biosynthesis protein ATIC (ATIC).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Bifunctional purine biosynthesis protein ATIC (ATIC).	[14]

References

• [1] AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet. 2004 Jun;74(6):1276-81. doi: 10.1086/421475. Epub 2004 Apr 26.
• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] 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.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [9] Methotrexate normalizes up-regulated folate pathway genes in rheumatoid arthritis. Arthritis Rheum. 2013 Nov;65(11):2791-802.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [13] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [14] 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.
• [15] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [18] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.