Details of Drug Off-Target (DOT)

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

• DOT Name: Bis(5'-adenosyl)-triphosphatase (FHIT)
• Synonyms: EC 3.6.1.29; AP3A hydrolase; AP3Aase; Adenosine 5'-monophosphoramidase FHIT; EC 3.9.1.-; Adenylylsulfatase; EC 3.6.2.1; Adenylylsulfate-ammonia adenylyltransferase; EC 2.7.7.51; Diadenosine 5',5'''-P1,P3-triphosphate hydrolase; Dinucleosidetriphosphatase; Fragile histidine triad protein
• Gene Name: FHIT
• UniProt ID: FHIT_HUMAN
• PDB ID: 1FHI; 1FIT; 2FHI; 2FIT; 3FIT; 4FIT; 5FIT; 6FIT; 7P8P
• EC Number: 2.7.7.51; 3.6.1.29; 3.6.2.1; 3.9.1.-
• Pfam ID: PF01230
• Sequence:
  MSFRFGQHLIKPSVVFLKTELSFALVNRKPVVPGHVLVCPLRPVERFHDLRPDEVADLFQ
  TTQRVGTVVEKHFHGTSLTFSMQDGPEAGQTVKHVHVHVLPRKAGDFHRNDSIYEELQKH
  DKEDFPASWRSEEEMAAEAAALRVYFQ
• Function: Possesses dinucleoside triphosphate hydrolase activity. Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP. Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP. Exhibits adenylylsulfatase activity, hydrolyzing adenosine 5'-phosphosulfate to yield AMP and sulfate. Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2. Exhibits adenylylsulfate-ammonia adenylyltransferase, catalyzing the ammonolysis of adenosine 5'-phosphosulfate resulting in the formation of adenosine 5'-phosphoramidate. Also catalyzes the ammonolysis of adenosine 5-phosphorofluoridate and diadenosine triphosphate. Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5. Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways. Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis. Induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity, it may in part come from the mitochondrial form, which sensitizes the low-affinity Ca(2+) transporters, enhancing mitochondrial calcium uptake. Functions as a tumor suppressor.
• Tissue Specificity: Low levels expressed in all tissues tested. Phospho-FHIT observed in liver and kidney, but not in brain and lung. Phospho-FHIT undetected in all tested human tumor cell lines.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Menadione	DMSJDTY	Approved	Bis(5'-adenosyl)-triphosphatase (FHIT) increases the response to substance of Menadione.	[12]
Aspirin	DM672AH	Approved	Bis(5'-adenosyl)-triphosphatase (FHIT) increases the Adverse reaction ADR of Aspirin.	[13]
Methamphetamine	DMPM4SK	Approved	Bis(5'-adenosyl)-triphosphatase (FHIT) affects the response to substance of Methamphetamine.	[14]
Phenytoin	DMNOKBV	Approved	Bis(5'-adenosyl)-triphosphatase (FHIT) increases the Hypersensitivity ADR of Phenytoin.	[15]

10 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 Bis(5'-adenosyl)-triphosphatase (FHIT).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[5]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[7]
Hydralazine	DMU8JGH	Approved	Hydralazine increases the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[10]
P1A	DMWCAQD	Discontinued in Phase 2	P1A affects the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[6]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Bis(5'-adenosyl)-triphosphatase (FHIT).	[11]

2 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 Bis(5'-adenosyl)-triphosphatase (FHIT).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Bis(5'-adenosyl)-triphosphatase (FHIT).	[6]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity. Int J Cancer. 2007 Jan 1;120(1):24-31. doi: 10.1002/ijc.22073.
• [7] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [8] A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes. BMC Cancer. 2005 Apr 29;5:44.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] 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.
• [11] Identification of early target genes of aflatoxin B1 in human hepatocytes, inter-individual variability and comparison with other genotoxic compounds. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):176-87.
• [12] Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12753-8. doi: 10.1073/pnas.0906484106. Epub 2009 Jul 21.
• [13] Genome-wide pharmacogenomic study of citalopram-induced side effects in STAR*D. Transl Psychiatry. 2012 Jul 3;2(7):e129. doi: 10.1038/tp.2012.57.
• [14] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.
• [15] Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.