Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9AGAIJ)

• DOT Name: Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP)
• Synonyms: hLHPP; EC 3.1.3.-; EC 3.6.1.1
• Gene Name: LHPP
• Related Disease:
  Advanced cancer
  Alcohol dependence
  Cervical cancer
  Cervical carcinoma
  Hepatocellular carcinoma
  Sexually transmitted infection
  Testicular germ cell tumor
  Type-1/2 diabetes
  Alcohol-induced disorders
  Alcohol-related disorders
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Major depressive disorder
  Neoplasm
• UniProt ID: LHPP_HUMAN
• PDB ID: 2X4D
• EC Number: 3.1.3.-; 3.6.1.1
• Pfam ID: PF13344 ; PF13242
• Sequence:
  MAPWGKRLAGVRGVLLDISGVLYDSGAGGGTAIAGSVEAVARLKRSRLKVRFCTNESQKS
  RAELVGQLQRLGFDISEQEVTAPAPAACQILKEQGLRPYLLIHDGVRSEFDQIDTSNPNC
  VVIADAGESFSYQNMNNAFQVLMELEKPVLISLGKGRYYKETSGLMLDVGPYMKALEYAC
  GIKAEVVGKPSPEFFKSALQAIGVEAHQAVMIGDDIVGDVGGAQRCGMRALQVRTGKFRP
  SDEHHPEVKADGYVDNLAEAVDLLLQHADK
• Function: Phosphatase that hydrolyzes imidodiphosphate, 3-phosphohistidine and 6-phospholysine. Has broad substrate specificity and can also hydrolyze inorganic diphosphate, but with lower efficiency.
• Tissue Specificity: Expressed in brain, and at lower levels in liver and kidney. Detected in thyroid (at protein level). Expressed in liver, kidney and moderately in brain.
• KEGG Pathway: Oxidative phosphorylation (hsa00190)
• Reactome Pathway: Pyrophosphate hydrolysis (R-HSA-71737)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Sexually transmitted infection	DISIVIAL	Strong	Biomarker	[2]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[5]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[1]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[2]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[2]
Bladder cancer	DISUHNM0	moderate	Biomarker	[6]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[6]
Major depressive disorder	DIS4CL3X	Limited	Genetic Variation	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Epirubicin	DMPDW6T	Approved	Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) increases the Neutropenia ADR of Epirubicin.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[18]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[19]
Purpurin	DMYWRL6	Investigative	Purpurin increases the expression of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP).	[15]

References

• [1] Specific Fluorescent Probe for Protein Histidine Phosphatase Activity.ACS Sens. 2019 Apr 26;4(4):1055-1062. doi: 10.1021/acssensors.9b00242. Epub 2019 Apr 3.
• [2] The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene.Neuropsychopharmacology. 2017 Feb;42(3):598-605. doi: 10.1038/npp.2016.153. Epub 2016 Aug 17.
• [3] Down-regulation of LHPP in cervical cancer influences cell proliferation, metastasis and apoptosis by modulating AKT.Biochem Biophys Res Commun. 2018 Sep 5;503(2):1108-1114. doi: 10.1016/j.bbrc.2018.06.127. Epub 2018 Aug 2.
• [4] Clinical value of LHPP-associated microRNAs combined with protein induced by vitamin K deficiency or antagonist-II in the diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma.J Clin Lab Anal. 2020 Feb;34(2):e23071. doi: 10.1002/jcla.23071. Epub 2019 Nov 6.
• [5] Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor.Nat Genet. 2017 Jul;49(7):1141-1147. doi: 10.1038/ng.3879. Epub 2017 Jun 12.
• [6] LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway.Biosci Rep. 2019 Jul 30;39(7):BSR20182270. doi: 10.1042/BSR20182270. Print 2019 Jul 31.
• [7] Association of LHPP genetic variation (rs35936514) with structural and functional connectivity of hippocampal-corticolimbic neural circuitry.Brain Imaging Behav. 2020 Aug;14(4):1025-1033. doi: 10.1007/s11682-019-00140-5.
• [8] Targeted nanoparticle-mediated LHPP for melanoma treatment.Int J Nanomedicine. 2019 May 10;14:3455-3468. doi: 10.2147/IJN.S196374. eCollection 2019.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] 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.
• [19] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [20] Purpurin binding interacts with LHPP protein that inhibits PI3K/AKT phosphorylation and induces apoptosis in colon cancer cells HCT-116. J Biochem Mol Toxicol. 2021 Mar;35(3):e22665. doi: 10.1002/jbt.22665. Epub 2020 Dec 28.
• [21] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.