Details of Drug Off-Target (DOT)

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

• DOT Name: 14 kDa phosphohistidine phosphatase (PHPT1)
• Synonyms: EC 3.9.1.3; Phosphohistidine phosphatase 1; PHPT1; Protein histidine phosphatase; PHP; Protein janus-A homolog
• Gene Name: PHPT1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Congenital hypothyroidism
  Herpes simplex infection
  Hypoparathyroidism
  Lung cancer
  Lung carcinoma
  Neoplasm
  Ocular melanoma
  Pseudohypoparathyroidism
  Pseudohypoparathyroidism type 1A
  Pseudopseudohypoparathyroidism
  Turner syndrome
  Usher syndrome
  Beckwith-Wiedemann syndrome
  Neonatal diabetes mellitus
  Pseudohypoparathyroidism type 1B
  Brachydactyly
  Obesity
• UniProt ID: PHP14_HUMAN
• PDB ID: 2AI6; 2HW4; 2NMM; 2OZW; 2OZX
• EC Number: 3.9.1.3
• Pfam ID: PF05005
• Sequence:
  MAVADLALIPDVDIDSDGVFKYVLIRVHSAPRSGAPAAESKEIVRGYKWAEYHADIYDKV
  SGDMQKQGCDCECLGGGRISHQSQDKKIHVYGYSMAYGPAQHAISTEKIKAKYPDYEVTW
  ANDGY
• Function: Exhibits phosphohistidine phosphatase activity.
• Tissue Specificity: Expressed abundantly in heart and skeletal muscle.
• BioCyc Pathway: MetaCyc:ENSG00000054148-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Congenital hypothyroidism	DISL5XVU	Strong	Genetic Variation	[2]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[3]
Hypoparathyroidism	DISICS0V	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Ocular melanoma	DISOHHFC	Strong	Biomarker	[6]
Pseudohypoparathyroidism	DIS183OJ	Strong	Biomarker	[7]
Pseudohypoparathyroidism type 1A	DISSOR3M	Strong	Genetic Variation	[8]
Pseudopseudohypoparathyroidism	DISRRO5I	Strong	Genetic Variation	[9]
Turner syndrome	DIS2035C	Strong	Biomarker	[10]
Usher syndrome	DIS9YIS7	Strong	Genetic Variation	[11]
Beckwith-Wiedemann syndrome	DISH15GR	moderate	Biomarker	[12]
Neonatal diabetes mellitus	DISFHF9K	moderate	Biomarker	[12]
Pseudohypoparathyroidism type 1B	DIS9LDXL	Disputed	Genetic Variation	[13]
Brachydactyly	DIS2533F	Limited	Biomarker	[7]
Obesity	DIS47Y1K	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 14 kDa phosphohistidine phosphatase (PHPT1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 14 kDa phosphohistidine phosphatase (PHPT1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of 14 kDa phosphohistidine phosphatase (PHPT1).	[24]

References

• [1] B-CAN: a resource sharing platform to improve the operation, visualization and integrated analysis of TCGA breast cancer data.Oncotarget. 2017 Oct 19;8(65):108778-108785. doi: 10.18632/oncotarget.21947. eCollection 2017 Dec 12.
• [2] A novel mutation causing pseudohypoparathyroidism 1A with congenital hypothyroidism and osteoma cutis.J Clin Res Pediatr Endocrinol. 2009;1(5):244-7. doi: 10.4274/jcrpe.v1i5.244. Epub 2009 Aug 6.
• [3] Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer's disease.J Neurosci. 2002 Nov 15;22(22):9733-41. doi: 10.1523/JNEUROSCI.22-22-09733.2002.
• [4] Bone Mineral Density and Its Serial Changes Are Associated With PTH Levels in Pseudohypoparathyroidism Type 1B Patients.J Bone Miner Res. 2018 Apr;33(4):743-752. doi: 10.1002/jbmr.3360. Epub 2018 Jan 3.
• [5] Knockdown of 14-kDa phosphohistidine phosphatase expression suppresses lung cancer cell growth in vivo possibly through inhibition of NF-B signaling pathway.Neoplasma. 2016;63(4):540-7. doi: 10.4149/neo_2016_407.
• [6] Embolization of variant hepatic arteries in patients undergoing percutaneous hepatic perfusion for unresectable liver metastases from ocular melanoma.Diagn Interv Radiol. 2019 Nov;25(6):451-458. doi: 10.5152/dir.2019.18138.
• [7] Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification.J Pediatr Endocrinol Metab. 2014 Nov;27(11-12):1089-94. doi: 10.1515/jpem-2014-0020.
• [8] Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity.J Bone Miner Res. 2018 Aug;33(8):1480-1488. doi: 10.1002/jbmr.3450. Epub 2018 Jun 7.
• [9] Pseudohypoparathyroidism Ia and hypercalcitoninemia.J Clin Endocrinol Metab. 2001 Jul;86(7):3091-6. doi: 10.1210/jcem.86.7.7690.
• [10] Dermatoglyphic and radiographic findings in a mother and daughter with pseudohypoparathyroidism.Clin Genet. 1978 Apr;13(4):359-68. doi: 10.1111/j.1399-0004.1978.tb01193.x.
• [11] Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate.Mol Ther Methods Clin Dev. 2018 Nov 20;13:1-13. doi: 10.1016/j.omtm.2018.11.003. eCollection 2019 Jun 14.
• [12] New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism.Eur J Endocrinol. 2010 Dec;163(6):953-62. doi: 10.1530/EJE-10-0435. Epub 2010 Sep 13.
• [13] Pseudohypoparathyroidism. New insights into an old disease.Endocrinol Metab Clin North Am. 2000 Sep;29(3):569-89. doi: 10.1016/s0889-8529(05)70151-1.
• [14] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] 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.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.