Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT251AAR)

• DOT Name: Inositol-pentakisphosphate 2-kinase (IPPK)
• Synonyms: EC 2.7.1.158; IPK1 homolog; Inositol-1,3,4,5,6-pentakisphosphate 2-kinase; Ins(1,3,4,5,6)P5 2-kinase; InsP5 2-kinase
• Gene Name: IPPK
• Related Disease:
  Cryptococcosis
  Type-1 diabetes
• UniProt ID: IPPK_HUMAN
• EC Number: 2.7.1.158
• Pfam ID: PF06090
• Sequence:
  MEEGKMDENEWGYHGEGNKSLVVAHAQRCVVLRFLKFPPNRKKTSEEIFQHLQNIVDFGK
  NVMKEFLGENYVHYGEVVQLPLEFVKQLCLKIQSERPESRCDKDLDTLSGYAMCLPNLTR
  LQTYRFAEHRPILCVEIKPKCGFIPFSSDVTHEMKHKVCRYCMHQHLKVATGKWKQISKY
  CPLDLYSGNKQRMHFALKSLLQEAQNNLKIFKNGELIYGCKDARSPVADWSELAHHLKPF
  FFPSNGLASGPHCTRAVIRELVHVITRVLLSGSDKGRAGTLSPGLGPQGPRVCEASPFSR
  SLRCQGKNTPERSGLPKGCLLYKTLQVQMLDLLDIEGLYPLYNRVERYLEEFPEERKTLQ
  IDGPYDEAFYQKLLDLSTEDDGTVAFALTKVQQYRVAMTAKDCSIMIALSPCLQDASSDQ
  RPVVPSSRSRFAFSVSVLDLDLKPYESIPHQYKLDGKIVNYYSKTVRAKDNAVMSTRFKE
  SEDCTLVLHKV
• Function: Phosphorylates Ins(1,3,4,5,6)P5 at position 2 to form Ins(1,2,3,4,5,6)P6 (InsP6 or phytate). InsP6 is involved in many processes such as mRNA export, non-homologous end-joining, endocytosis, ion channel regulation. It also protects cells from TNF-alpha-induced apoptosis.
• Tissue Specificity: Ubiquitously expressed, with high expression in heart, brain, testis and placenta.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Synthesis of IPs in the nucleus (R-HSA-1855191)
  Synthesis of pyrophosphates in the cytosol (R-HSA-1855167)
• BioCyc Pathway: MetaCyc:HS05071-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cryptococcosis	DISDYDTK	Strong	Biomarker	[1]
Type-1 diabetes	DIS7HLUB	Disputed	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Inositol-pentakisphosphate 2-kinase (IPPK).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Inositol-pentakisphosphate 2-kinase (IPPK).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Inositol-pentakisphosphate 2-kinase (IPPK).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Inositol-pentakisphosphate 2-kinase (IPPK).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Inositol-pentakisphosphate 2-kinase (IPPK).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Inositol-pentakisphosphate 2-kinase (IPPK).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inositol-pentakisphosphate 2-kinase (IPPK).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Inositol-pentakisphosphate 2-kinase (IPPK).	[9]

References

• [1] Crystal structure of inositol 1,3,4,5,6-pentakisphosphate 2-kinase from Cryptococcus neoformans.J Struct Biol. 2017 Nov;200(2):118-123. doi: 10.1016/j.jsb.2017.09.004. Epub 2017 Sep 15.
• [2] Urine inositol pentakisphosphate 2-kinase and changes in kidney structure in early diabetic kidney disease in type 1 diabetes.Am J Physiol Renal Physiol. 2018 Nov 1;315(5):F1484-F1492. doi: 10.1152/ajprenal.00183.2018. Epub 2018 Aug 22.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] 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.
• [9] 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.
• [10] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.