Details of Drug Off-Target (DOT)

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

• DOT Name: Multiple inositol polyphosphate phosphatase 1 (MINPP1)
• Synonyms: EC 3.1.3.62; 2,3-bisphosphoglycerate 3-phosphatase; 2,3-BPG phosphatase; EC 3.1.3.80
• Gene Name: MINPP1
• Related Disease:
  Pontocerebellar hypoplasia, type 16
  Pontocerebellar hypoplasia type 7
  Thyroid cancer, nonmedullary, 2
• UniProt ID: MINP1_HUMAN
• EC Number: 3.1.3.62; 3.1.3.80
• Pfam ID: PF00328
• Sequence:
  MLRAPGCLLRTSVAPAAALAAALLSSLARCSLLEPRDPVASSLSPYFGTKTRYEDVNPVL
  LSGPEAPWRDPELLEGTCTPVQLVALIRHGTRYPTVKQIRKLRQLHGLLQARGSRDGGAS
  STGSRDLGAALADWPLWYADWMDGQLVEKGRQDMRQLALRLASLFPALFSRENYGRLRLI
  TSSKHRCMDSSAAFLQGLWQHYHPGLPPPDVADMEFGPPTVNDKLMRFFDHCEKFLTEVE
  KNATALYHVEAFKTGPEMQNILKKVAATLQVPVNDLNADLIQVAFFTCSFDLAIKGVKSP
  WCDVFDIDDAKVLEYLNDLKQYWKRGYGYTINSRSSCTLFQDIFQHLDKAVEQKQRSQPI
  SSPVILQFGHAETLLPLLSLMGYFKDKEPLTAYNYKKQMHRKFRSGLIVPYASNLIFVLY
  HCENAKTPKEQFRVQMLLNEKVLPLAYSQETVSFYEDLKNHYKDILQSCQTSEECELARA
  NSTSDEL
• Function: Multiple inositol polyphosphate phosphatase that hydrolyzes 1D-myo-inositol 1,3,4,5,6-pentakisphosphate (InsP5[2OH]) and 1D-myo-inositol hexakisphosphate (InsP6) to a range of less phosphorylated inositol phosphates. This regulates the availability of these various small molecule second messengers and metal chelators which control many aspects of cell physiology. Has a weak in vitro activity towards 1D-myo-inositol 1,4,5-trisphosphate which is unlikely to be physiologically relevant. By regulating intracellular inositol polyphosphates pools, which act as metal chelators, it may control the availability of intracellular calcium and iron, which are important for proper neuronal development and homeostasis. May have a dual substrate specificity, and function as a 2,3-bisphosphoglycerate 3-phosphatase hydrolyzing 2,3-bisphosphoglycerate to 2-phosphoglycerate. 2,3-bisphosphoglycerate (BPG) is formed as part of the Rapoport-Luebering glycolytic bypass and is a regulator of systemic oxygen homeostasis as the major allosteric effector of hemoglobin.
• Tissue Specificity: Widely expressed with highest levels in kidney, liver, cerebellum and placenta.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of IPs in the ER lumen (R-HSA-1855231)
• BioCyc Pathway: MetaCyc:HS03025-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pontocerebellar hypoplasia, type 16	DISQNDTP	Strong	Autosomal recessive	[1]
Pontocerebellar hypoplasia type 7	DISXFITF	Supportive	Autosomal recessive	[2]
Thyroid cancer, nonmedullary, 2	DISJ3RYM	No Known	Unknown	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[13]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Multiple inositol polyphosphate phosphatase 1 (MINPP1).	[17]

References

• [1] MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia. Nat Commun. 2020 Nov 30;11(1):6087. doi: 10.1038/s41467-020-19919-y.
• [2] Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1. Eur J Hum Genet. 2021 Mar;29(3):411-421. doi: 10.1038/s41431-020-00749-x. Epub 2020 Nov 9.
• [3] Exome sequencing of a large family identifies potential candidate genes contributing risk to bipolar disorder. Gene. 2018 Mar 1;645:119-123. doi: 10.1016/j.gene.2017.12.025. Epub 2017 Dec 14.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [11] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [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] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.