Details of Drug Off-Target (DOT)

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

• DOT Name: Phosphoribosylformylglycinamidine synthase (PFAS)
• Synonyms: FGAM synthase; FGAMS; EC 6.3.5.3; Formylglycinamide ribonucleotide amidotransferase; FGAR amidotransferase; FGAR-AT; Formylglycinamide ribotide amidotransferase; Phosphoribosylformylglycineamide amidotransferase
• Gene Name: PFAS
• UniProt ID: PUR4_HUMAN
• EC Number: 6.3.5.3
• Pfam ID: PF02769 ; PF18072 ; PF18076 ; PF13507
• Sequence:
  MSPVLHFYVRPSGHEGAAPGHTRRKLQGKLPELQGVETELCYNVNWTAEALPSAEETKKL
  MWLFGCPLLLDDVARESWLLPGSNDLLLEVGPRLNFSTPTSTNIVSVCRATGLGPVDRVE
  TTRRYRLSFAHPPSAEVEAIALATLHDRMTEQHFPHPIQSFSPESMPEPLNGPINILGEG
  RLALEKANQELGLALDSWDLDFYTKRFQELQRNPSTVEAFDLAQSNSEHSRHWFFKGQLH
  VDGQKLVHSLFESIMSTQESSNPNNVLKFCDNSSAIQGKEVRFLRPEDPTRPSRFQQQQG
  LRHVVFTAETHNFPTGVCPFSGATTGTGGRIRDVQCTGRGAHVVAGTAGYCFGNLHIPGY
  NLPWEDPSFQYPGNFARPLEVAIEASNGASDYGNKFGEPVLAGFARSLGLQLPDGQRREW
  IKPIMFSGGIGSMEADHISKEAPEPGMEVVKVGGPVYRIGVGGGAASSVQVQGDNTSDLD
  FGAVQRGDPEMEQKMNRVIRACVEAPKGNPICSLHDQGAGGNGNVLKELSDPAGAIIYTS
  RFQLGDPTLNALEIWGAEYQESNALLLRSPNRDFLTHVSARERCPACFVGTITGDRRIVL
  VDDRECPVRRNGQGDAPPTPLPTPVDLELEWVLGKMPRKEFFLQRKPPMLQPLALPPGLS
  VHQALERVLRLPAVASKRYLTNKVDRSVGGLVAQQQCVGPLQTPLADVAVVALSHEELIG
  AATALGEQPVKSLLDPKVAARLAVAEALTNLVFALVTDLRDVKCSGNWMWAAKLPGEGAA
  LADACEAMVAVMAALGVAVDGGKDSLSMAARVGTETVRAPGSLVISAYAVCPDITATVTP
  DLKHPEGRGHLLYVALSPGQHRLGGTALAQCFSQLGEHPPDLDLPENLVRAFSITQGLLK
  DRLLCSGHDVSDGGLVTCLLEMAFAGNCGLQVDVPVPRVDVLSVLFAEEPGLVLEVQEPD
  LAQVLKRYRDAGLHCLELGHTGEAGPHAMVRVSVNGAVVLEEPVGELRALWEETSFQLDR
  LQAEPRCVAEEERGLRERMGPSYCLPPTFPKASVPREPGGPSPRVAILREEGSNGDREMA
  DAFHLAGFEVWDVTMQDLCSGAIGLDTFRGVAFVGGFSYADVLGSAKGWAAAVTFHPRAG
  AELRRFRKRPDTFSLGVCNGCQLLALLGWVGGDPNEDAAEMGPDSQPARPGLLLRHNLSG
  RYESRWASVRVGPGPALMLRGMEGAVLPVWSAHGEGYVAFSSPELQAQIEARGLAPLHWA
  DDDGNPTEQYPLNPNGSPGGVAGICSCDGRHLAVMPHPERAVRPWQWAWRPPPFDTLTTS
  PWLQLFINARNWTLEGSC
• Function: Phosphoribosylformylglycinamidine synthase involved in the purines biosynthetic pathway. Catalyzes the ATP-dependent conversion of formylglycinamide ribonucleotide (FGAR) and glutamine to yield formylglycinamidine ribonucleotide (FGAM) and glutamate.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Purine ribonucleoside monophosphate biosynthesis (R-HSA-73817)
• BioCyc Pathway: MetaCyc:HS11329-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Phosphoribosylformylglycinamidine synthase (PFAS) affects the response to substance of Methotrexate.	[21]

22 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 Phosphoribosylformylglycinamidine synthase (PFAS).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[14]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[14]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Phosphoribosylformylglycinamidine synthase (PFAS).	[20]

1 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 Phosphoribosylformylglycinamidine synthase (PFAS).	[9]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [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] 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.
• [10] 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.
• [11] Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. Eur Rev Med Pharmacol Sci. 2014;18(24):3877-88.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [21] Gene expression profiling of leukemia T-cells resistant to methotrexate and 7-hydroxymethotrexate reveals alterations that preserve intracellular levels of folate and nucleotide biosynthesis. Biochem Pharmacol. 2009 Apr 15;77(8):1410-7.