Details of Drug Off-Target (DOT)

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

• DOT Name: Inositol polyphosphate multikinase (IPMK)
• Synonyms: EC 2.7.1.140; EC 2.7.1.151; EC 2.7.1.153; Inositol 1,3,4,6-tetrakisphosphate 5-kinase
• Gene Name: IPMK
• Related Disease: Hereditary neuroendocrine tumor of small intestine
• UniProt ID: IPMK_HUMAN
• PDB ID: 5W2G; 5W2H; 5W2I; 6E7F; 6M88; 6M89; 6M8A; 6M8B; 6M8C; 6M8D; 6M8E
• EC Number: 2.7.1.140; 2.7.1.151; 2.7.1.153
• Pfam ID: PF03770
• Sequence:
  MATEPPSPLRVEAPGPPEMRTSPAIESTPEGTPQPAGGRLRFLNGCVPLSHQVAGHMYGK
  DKVGILQHPDGTVLKQLQPPPRGPRELEFYNMVYAADCFDGVLLELRKYLPKYYGIWSPP
  TAPNDLYLKLEDVTHKFNKPCIMDVKIGQKSYDPFASSEKIQQQVSKYPLMEEIGFLVLG
  MRVYHVHSDSYETENQHYGRSLTKETIKDGVSRFFHNGYCLRKDAVAASIQKIEKILQWF
  ENQKQLNFYASSLLFVYEGSSQPTTTKLNDRTLAEKFLSKGQLSDTEVLEYNNNFHVLSS
  TANGKIESSVGKSLSKMYARHRKIYTKKHHSQTSLKVENLEQDNGWKSMSQEHLNGNVLS
  QLEKVFYHLPTGCQEIAEVEVRMIDFAHVFPSNTIDEGYVYGLKHLISVLRSILDN
• Function: Inositol phosphate kinase with a broad substrate specificity. Phosphorylates inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) first to inositol 1,3,4,5-tetrakisphosphate and then to inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5). Phosphorylates inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4). Phosphorylates inositol 1,4,5,6-tetrakisphosphate (Ins(1,4,5,6)P4). Phosphorylates glycero-3-phospho-1D-myo-inositol 4,5-bisphosphate to glycero-3-phospho-1D-myo-inositol 3,4,5-trisphosphate. Plays an important role in MLKL-mediated necroptosis via its role in the biosynthesis of inositol pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6). Binding of these highly phosphorylated inositol phosphates to MLKL mediates the release of an N-terminal auto-inhibitory region, leading to activation of the kinase. Essential for activated phospho-MLKL to oligomerize and localize to the cell membrane during necroptosis. Required for normal embryonic development, probably via its role in the biosynthesis of inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) and inositol hexakisphosphate (InsP6).
• Tissue Specificity: Ubiquitous, with the highest expression in skeletal muscle, liver, placenta, lung, peripheral blood leukocytes, kidney, spleen and colon.
• 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)
• BioCyc Pathway: MetaCyc:HS07712-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary neuroendocrine tumor of small intestine	DIS82J8L	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Inositol polyphosphate multikinase (IPMK).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Inositol polyphosphate multikinase (IPMK).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Inositol polyphosphate multikinase (IPMK).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Inositol polyphosphate multikinase (IPMK).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Inositol polyphosphate multikinase (IPMK).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Inositol polyphosphate multikinase (IPMK).	[7]

References

• [1] A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase. Gastroenterology. 2015 Jul;149(1):67-78. doi: 10.1053/j.gastro.2015.04.008. Epub 2015 Apr 9.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.