Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMZN747)

• DOT Name: Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS)
• Synonyms: PAICS
• Gene Name: PAICS
• Related Disease:
  46,XY disorder of sex development
  Advanced cancer
  Androgen insensitivity syndrome
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Gonadal dysgenesis
  Neoplasm
  Partial androgen insensitivity syndrome
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Turner syndrome
  46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency
  Complete androgen insensitivity syndrome
  Disorder of sexual differentiation
  Cryptorchidism
  Stroke
• UniProt ID: PUR6_HUMAN
• PDB ID: 2H31; 6YB8; 6YB9; 7ALE
• EC Number: 4.1.1.21; 6.3.2.6
• Pfam ID: PF00731 ; PF01259
• Sequence:
  MATAEVLNIGKKLYEGKTKEVYELLDSPGKVLLQSKDQITAGNAARKNHLEGKAAISNKI
  TSCIFQLLQEAGIKTAFTRKCGETAFIAPQCEMIPIEWVCRRIATGSFLKRNPGVKEGYK
  FYPPKVELFFKDDANNDPQWSEEQLIAAKFCFAGLLIGQTEVDIMSHATQAIFEILEKSW
  LPQNCTLVDMKIEFGVDVTTKEIVLADVIDNDSWRLWPSGDRSQQKDKQSYRDLKEVTPE
  GLQMVKKNFEWVAERVELLLKSESQCRVVVLMGSTSDLGHCEKIKKACGNFGIPCELRVT
  SAHKGPDETLRIKAEYEGDGIPTVFVAVAGRSNGLGPVMSGNTAYPVISCPPLTPDWGVQ
  DVWSSLRLPSGLGCSTVLSPEGSAQFAAQIFGLSNHLVWSKLRASILNTWISLKQADKKI
  RECNL
• Function: Bifunctional phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase catalyzing two reactions of the de novo purine biosynthetic pathway.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Purine ribonucleoside monophosphate biosynthesis (R-HSA-73817)
• BioCyc Pathway: MetaCyc:HS05155-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY disorder of sex development	DIS78CGG	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Androgen insensitivity syndrome	DISUZBBO	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Gonadal dysgenesis	DISIL2ZI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Partial androgen insensitivity syndrome	DISQ1113	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[7]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[7]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[8]
Turner syndrome	DIS2035C	Strong	Biomarker	[5]
46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency	DISO74X3	moderate	Biomarker	[1]
Complete androgen insensitivity syndrome	DISQL418	moderate	Biomarker	[3]
Disorder of sexual differentiation	DISRMAEZ	moderate	Genetic Variation	[3]
Cryptorchidism	DISYUD2P	Limited	Genetic Variation	[9]
Stroke	DISX6UHX	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[18]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[19]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[22]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[23]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[26]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[27]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Bifunctional phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS).	[28]

References

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• [2] SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer.Front Pharmacol. 2018 Feb 2;8:956. doi: 10.3389/fphar.2017.00956. eCollection 2017.
• [3] A novel mutation (c.T3816 > C) in the androgen receptor gene in a 46,XY female patient with androgen insensitivity syndrome.Endokrynol Pol. 2013;64(5):398-402. doi: 10.5603/EP.2013.0023.
• [4] Systematic functional perturbations uncover a prognostic genetic network driving human breast cancer.Oncotarget. 2017 Mar 15;8(13):20572-20587. doi: 10.18632/oncotarget.16244.
• [5] Increased risk of gonadal malignancy and prophylactic gonadectomy: a study of 102 phenotypic female patients with Y chromosome or Y-derived sequences.Hum Reprod. 2014 Jul;29(7):1413-9. doi: 10.1093/humrep/deu109. Epub 2014 May 14.
• [6] A functional yeast survival screen of tumor-derived cDNA libraries designed to identify anti-apoptotic mammalian oncogenes.PLoS One. 2013 May 22;8(5):e64873. doi: 10.1371/journal.pone.0064873. Print 2013.
• [7] Radioablation +/- hormonotherapy for prostate cancer oligorecurrences (Radiosa trial): potential of imaging and biology (AIRC IG-22159).BMC Cancer. 2019 Sep 10;19(1):903. doi: 10.1186/s12885-019-6117-z.
• [8] An androgen receptor gene mutation (A645D) in a boy with a normal phenotype.Hum Mutat. 1998;11(4):339.
• [9] Postnatal germ cell development during first 18months of life in testes from boys with non-syndromic cryptorchidism and complete or partial androgen insensitivity syndrome.J Pediatr Surg. 2019 Aug;54(8):1654-1659. doi: 10.1016/j.jpedsurg.2018.12.011. Epub 2019 Jan 3.
• [10] PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a Randomized, Double-Blind Placebo-Controlled Clinical Trial.Stroke. 2017 Apr;48(4):977-982. doi: 10.1161/STROKEAHA.116.015957. Epub 2017 Mar 13.
• [11] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [12] 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.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [14] 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.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] 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.
• [18] Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561-7.
• [19] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [20] 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.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [24] 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.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] 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.
• [28] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.