Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT06HYH8)

• DOT Name: Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1)
• Synonyms: EC 2.7.4.24; Diphosphoinositol pentakisphosphate kinase 1; Histidine acid phosphatase domain-containing protein 2A; IP6 kinase; Inositol pyrophosphate synthase 1; InsP6 and PP-IP5 kinase 1; VIP1 homolog; hsVIP1
• Gene Name: PPIP5K1
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Hepatocellular carcinoma
  Human papillomavirus infection
  Liver cirrhosis
  Polycythemia vera
  Trichomoniasis
  Zika virus infection
  Bronchiolitis
  Chronic hepatitis B virus infection
  Melanoma
  Non-small-cell lung cancer
• UniProt ID: VIP1_HUMAN
• EC Number: 2.7.4.24
• Pfam ID: PF00328 ; PF18086
• Sequence:
  MWSLTASEGESTTAHFFLGAGDEGLGTRGIGMRPEESDSELLEDEEDEVPPEPQIIVGIC
  AMTKKSKSKPMTQILERLCRFDYLTVVILGEDVILNEPVENWPSCHCLISFHSKGFPLDK
  AVAYSKLRNPFLINDLAMQYYIQDRREVYRILQEEGIDLPRYAVLNRDPARPEECNLIEG
  EDQVEVNGAVFPKPFVEKPVSAEDHNVYIYYPSSAGGGSQRLFRKIGSRSSVYSPESSVR
  KTGSYIYEEFMPTDGTDVKVYTVGPDYAHAEARKSPALDGKVERDSEGKEIRYPVMLTAM
  EKLVARKVCVAFKQTVCGFDLLRANGHSFVCDVNGFSFVKNSMKYYDDCAKILGNTIMRE
  LAPQFQIPWSIPTEAEDIPIVPTTSGTMMELRCVIAIIRHGDRTPKQKMKMEVKHPRFFA
  LFEKHGGYKTGKLKLKRPEQLQEVLDITRLLLAELEKEPGGEIEEKTGKLEQLKSVLEMY
  GHFSGINRKVQLTYYPHGVKASNEGQDPQRETLAPSLLLVLKWGGELTPAGRVQAEELGR
  AFRCMYPGGQGDYAGFPGCGLLRLHSTFRHDLKIYASDEGRVQMTAAAFAKGLLALEGEL
  TPILVQMVKSANMNGLLDSDGDSLSSCQHRVKARLHHILQQDAPFGPEDYDQLAPTRSTS
  LLNSMTIIQNPVKVCDQVFALIENLTHQIRERMQDPRSVDLQLYHSETLELMLQRWSKLE
  RDFRQKSGRYDISKIPDIYDCVKYDVQHNGSLGLQGTAELLRLSKALADVVIPQEYGISR
  EEKLEIAVGFCLPLLRKILLDLQRTHEDESVNKLHPLCYLRYSRGVLSPGRHVRTRLYFT
  SESHVHSLLSVFRYGGLLDETQDAQWQRALDYLSAISELNYMTQIVIMLYEDNTQDPLSE
  ERFHVELHFSPGVKGVEEEGSAPAGCGFRPASSENEEMKTNQGSMENLCPGKASDEPDRA
  LQTSPQPPEGPGLPRRSPLIRNRKAGSMEVLSETSSSRPGGYRLFSSSRPPTEMKQSGLG
  SQCTGLFSTTVLGGSSSAPNLQDYARSHGKKLPPASLKHRDELLFVPAVKRFSVSFAKHP
  TNGFEGCSMVPTIYPLETLHNALSLRQVSEFLSRVCQRHTDAQAQASAALFDSMHSSQAS
  DNPFSPPRTLHSPPLQLQQRSEKPPWYSSGPSSTVSSAGPSSPTTVDGNSQFGFSDQPSL
  NSHVAEEHQGLGLLQETPGSGAQELSIEGEQELFEPNQSPQVPPMETSQPYEEVSQPCQE
  VPDISQPCQDISEALSQPCQKVPDISQQCQENHDNGNHTCQEVPHISQPCQKSSQLCQKV
  SEEVCQLCLENSEEVSQPCQGVSVEVGKLVHKFHVGVGSLVQETLVEVGSPAEEIPEEVI
  QPYQEFSVEVGRLAQETSAINLLSQGIPEIDKPSQEFPEEIDLQAQEVPEEIN
• Function: Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis-diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at position 1 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates PP-InsP5 at position 1, produced by IP6Ks from InsP6, to produce (PP)2-InsP4. Activated when cells are exposed to hyperosmotic stress.
• Tissue Specificity: Widely expressed, with a higher expression in skeletal muscle, heart and brain.
• KEGG Pathway: Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway: Synthesis of pyrophosphates in the cytosol (R-HSA-1855167)
• BioCyc Pathway: MetaCyc:HS09822-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Strong	Genetic Variation	[1]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Human papillomavirus infection	DISX61LX	Strong	Genetic Variation	[1]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[2]
Polycythemia vera	DISB5FPO	Strong	Biomarker	[3]
Trichomoniasis	DIS9HBNL	Strong	Biomarker	[4]
Zika virus infection	DISQUCTY	Strong	Biomarker	[5]
Bronchiolitis	DISEE9BG	Limited	Biomarker	[6]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Altered Expression	[2]
Melanoma	DIS1RRCY	Limited	Altered Expression	[7]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[8]

6 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 Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 1 (PPIP5K1).	[16]

References

• [1] Decline in prevalence of human papillomavirus infection following vaccination among Australian Indigenous women, a population at higher risk of cervical cancer: The VIP-I study.Vaccine. 2018 Jul 5;36(29):4311-4316. doi: 10.1016/j.vaccine.2018.05.104. Epub 2018 Jun 5.
• [2] Up-regulation of RIP1 and IPS-1 in chronic HBV infected patients.Genet Mol Biol. 2019 Apr-Jun;42(2):337-343. doi: 10.1590/1678-4685-GMB-2018-0071. Epub 2019 Aug 19.
• [3] The TLR3/TICAM-1 pathway is mandatory for innate immune responses to poliovirus infection.J Immunol. 2011 Nov 15;187(10):5320-7. doi: 10.4049/jimmunol.1101503. Epub 2011 Oct 12.
• [4] A novel 6-pyrophosphorylating IP6 kinase (IP6-6K) discovered in the protozoon Trichomonas vaginalis.Mol Biochem Parasitol. 2019 Jan;227:53-63. doi: 10.1016/j.molbiopara.2018.12.004. Epub 2018 Dec 26.
• [5] Predominant role of IPS-1 over TRIF adaptor proteins in early innate immune response against Zika virus in mice.J Gen Virol. 2018 Feb;99(2):209-218. doi: 10.1099/jgv.0.000992. Epub 2018 Jan 3.
• [6] The Absence of Interferon- Promotor Stimulator-1 (IPS-1) Predisposes to Bronchiolitis and Asthma-like Pathology in Response to Pneumoviral Infection in Mice.Sci Rep. 2017 May 24;7(1):2353. doi: 10.1038/s41598-017-02564-9.
• [7] Agaricus blazei Murill Polysaccharides Protect Against Cadmium-Induced Oxidative Stress and Inflammatory Damage in Chicken Spleens.Biol Trace Elem Res. 2018 Jul;184(1):247-258. doi: 10.1007/s12011-017-1189-6. Epub 2017 Oct 14.
• [8] (Stearyl, Norleucine17)VIP hybrid antagonizes VIP receptors on non-small cell lung cancer cells.Life Sci. 1997;61(17):1657-66. doi: 10.1016/s0024-3205(97)00771-6.
• [9] 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.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [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] 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.
• [13] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.