Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ3L42N)

• DOT Name: Inositol polyphosphate 5-phosphatase OCRL (OCRL)
• Synonyms: EC 3.1.3.36; EC 3.1.3.56; Inositol polyphosphate 5-phosphatase OCRL-1; OCRL-1; Lowe oculocerebrorenal syndrome protein; Phosphatidylinositol 3,4,5-triphosphate 5-phosphatase; EC 3.1.3.86
• Gene Name: OCRL
• Related Disease:
  Dent disease type 2
  Glaucoma/ocular hypertension
  Oculocerebrorenal syndrome
  Adult glioblastoma
  Autism
  Cataract
  Congenital glaucoma
  Dent disease
  Fanconi's anemia
  Glioblastoma multiforme
  Intellectual disability
  Kidney failure
  Listeriosis
  Nephrocalcinosis
  Osteoarthritis
  Primary Fanconi syndrome
  Subcortical band heterotopia
  Trichohepatoenteric syndrome
  Chronic kidney disease
  Cryptorchidism
  Dent disease type 1
  X-linked intellectual disability
• UniProt ID: OCRL_HUMAN
• PDB ID: 2KIE; 2QV2; 3QBT; 3QIS; 4CMN
• EC Number: 3.1.3.36; 3.1.3.56; 3.1.3.86
• Pfam ID: PF21310 ; PF16726 ; PF00620
• Sequence:
  MEPPLPVGAQPLATVEGMEMKGPLREPCALTLAQRNGQYELIIQLHEKEQHVQDIIPINS
  HFRCVQEAEETLLIDIASNSGCKIRVQGDWIRERRFEIPDEEHCLKFLSAVLAAQKAQSQ
  LLVPEQKDSSSWYQKLDTKDKPSVFSGLLGFEDNFSSMNLDKKINSQNQPTGIHREPPPP
  PFSVNKMLPREKEASNKEQPKVTNTMRKLFVPNTQSGQREGLIKHILAKREKEYVNIQTF
  RFFVGTWNVNGQSPDSGLEPWLNCDPNPPDIYCIGFQELDLSTEAFFYFESVKEQEWSMA
  VERGLHSKAKYKKVQLVRLVGMMLLIFARKDQCRYIRDIATETVGTGIMGKMGNKGGVAV
  RFVFHNTTFCIVNSHLAAHVEDFERRNQDYKDICARMSFVVPNQTLPQLNIMKHEVVIWL
  GDLNYRLCMPDANEVKSLINKKDLQRLLKFDQLNIQRTQKKAFVDFNEGEIKFIPTYKYD
  SKTDRWDSSGKCRVPAWCDRILWRGTNVNQLNYRSHMELKTSDHKPVSALFHIGVKVVDE
  RRYRKVFEDSVRIMDRMENDFLPSLELSRREFVFENVKFRQLQKEKFQISNNGQVPCHFS
  FIPKLNDSQYCKPWLRAEPFEGYLEPNETVDISLDVYVSKDSVTILNSGEDKIEDILVLH
  LDRGKDYFLTISGNYLPSCFGTSLEALCRMKRPIREVPVTKLIDLEEDSFLEKEKSLLQM
  VPLDEGASERPLQVPKEIWLLVDHLFKYACHQEDLFQTPGMQEELQQIIDCLDTSIPETI
  PGSNHSVAEALLIFLEALPEPVICYELYQRCLDSAYDPRICRQVISQLPRCHRNVFRYLM
  AFLRELLKFSEYNSVNANMIATLFTSLLLRPPPNLMARQTPSDRQRAIQFLLGFLLGSEE
  D
• Function: Catalyzes the hydrolysis of the 5-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2. Able also to hydrolyze the 5-phosphate of inositol 1,4,5-trisphosphate and of inositol 1,3,4,5-tetrakisphosphate. Regulates traffic in the endosomal pathway by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with endosomes. Involved in primary cilia assembly. Acts as a regulator of phagocytosis, hydrolyzing PtdIns(4,5)P2 to promote phagosome closure, through attenuation of PI3K signaling.
• Tissue Specificity: Brain, skeletal muscle, heart, kidney, lung, placenta and fibroblasts. Expressed in the retina and the retinal pigment epithelium.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Synthesis of IP2, IP, and Ins in the cytosol (R-HSA-1855183)
  Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS04546-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dent disease type 2	DISJFNHL	Definitive	X-linked	[1]
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Biomarker	[2]
Oculocerebrorenal syndrome	DIS8TEDY	Definitive	X-linked	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Cataract	DISUD7SL	Strong	Genetic Variation	[6]
Congenital glaucoma	DISHN3GO	Strong	Genetic Variation	[7]
Dent disease	DISRDLFN	Strong	Genetic Variation	[8]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[9]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[10]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[11]
Listeriosis	DISKMQBM	Strong	Biomarker	[12]
Nephrocalcinosis	DIS5ZVJP	Strong	Genetic Variation	[13]
Osteoarthritis	DIS05URM	Strong	Biomarker	[14]
Primary Fanconi syndrome	DISR144Y	Strong	Genetic Variation	[9]
Subcortical band heterotopia	DISHN7JS	Strong	Genetic Variation	[15]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[16]
Chronic kidney disease	DISW82R7	moderate	Genetic Variation	[17]
Cryptorchidism	DISYUD2P	moderate	Altered Expression	[18]
Dent disease type 1	DISNGJIQ	Limited	Genetic Variation	[19]
X-linked intellectual disability	DISYJBY3	Limited	Genetic Variation	[20]

7 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 polyphosphate 5-phosphatase OCRL (OCRL).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[23]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[25]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Inositol polyphosphate 5-phosphatase OCRL (OCRL).	[27]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe.PLoS One. 2013 Jun 21;8(6):e66727. doi: 10.1371/journal.pone.0066727. Print 2013.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Lipid phosphatases SKIP and SHIP2 regulate fibronectin-dependent cell migration in glioblastoma.FEBS J. 2019 Mar;286(6):1120-1135. doi: 10.1111/febs.14769. Epub 2019 Feb 16.
• [5] Duplication of OCRL and adjacent genes associated with autism but not Lowe syndrome.Am J Med Genet A. 2012 Oct;158A(10):2602-5. doi: 10.1002/ajmg.a.35566. Epub 2012 Sep 10.
• [6] Prevalence of Congenital Ocular Anomalies among Children with Genetic Disorders: An Egyptian Study.Semin Ophthalmol. 2018;33(5):613-619. doi: 10.1080/08820538.2017.1375124. Epub 2017 Oct 9.
• [7] Ocular Pathology of Oculocerebrorenal Syndrome of Lowe: Novel Mutations and Genotype-Phenotype Analysis.Sci Rep. 2017 May 4;7(1):1442. doi: 10.1038/s41598-017-01447-3.
• [8] Genetic Analysis of Dent's Disease and Functional Research of CLCN5 Mutations.DNA Cell Biol. 2017 Dec;36(12):1151-1158. doi: 10.1089/dna.2017.3731. Epub 2017 Oct 23.
• [9] A role for OCRL in glomerular function and disease.Pediatr Nephrol. 2020 Apr;35(4):641-648. doi: 10.1007/s00467-019-04317-4. Epub 2019 Dec 6.
• [10] OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease.Hum Mol Genet. 2019 Jun 15;28(12):1931-1946. doi: 10.1093/hmg/ddy449.
• [11] Lowe Syndrome protein OCRL1 supports maturation of polarized epithelial cells.PLoS One. 2011;6(8):e24044. doi: 10.1371/journal.pone.0024044. Epub 2011 Aug 25.
• [12] Phosphatidylinositol 5-phosphatase oculocerebrorenal syndrome of Lowe protein (OCRL) controls actin dynamics during early steps of Listeria monocytogenes infection.J Biol Chem. 2012 Apr 13;287(16):13128-36. doi: 10.1074/jbc.M111.315788. Epub 2012 Feb 18.
• [13] Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction.Clin J Am Soc Nephrol. 2008 Sep;3(5):1430-6. doi: 10.2215/CJN.00520108. Epub 2008 May 14.
• [14] Down-regulation of Rac GTPase-activating protein OCRL1 causes aberrant activation of Rac1 in osteoarthritis development.Arthritis Rheumatol. 2015 May;67(8):2154-63. doi: 10.1002/art.39174.
• [15] Pigmentary mosaicism, subcortical band heterotopia, and brain cystic lesions.Pediatr Neurol. 2009 May;40(5):383-6. doi: 10.1016/j.pediatrneurol.2008.11.006.
• [16] A novel pathogenic DNA variation in the OCRL1 gene in Lowe syndrome.J Clin Res Pediatr Endocrinol. 2011;3(1):29-31. doi: 10.4274/jcrpe.v3i1.06. Epub 2011 Feb 23.
• [17] Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort.Nephrol Dial Transplant. 2018 Jan 1;33(1):85-94. doi: 10.1093/ndt/gfw350.
• [18] Renal manifestations of Dent disease and Lowe syndrome.Pediatr Nephrol. 2008 Feb;23(2):243-9. doi: 10.1007/s00467-007-0686-9. Epub 2007 Nov 24.
• [19] Muscle involvement in Dent disease 2.Pediatr Nephrol. 2014 Nov;29(11):2127-32. doi: 10.1007/s00467-014-2841-4. Epub 2014 Jun 7.
• [20] Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network.Hum Mol Genet. 2003 Oct 1;12(19):2449-56. doi: 10.1093/hmg/ddg250. Epub 2003 Jul 29.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] 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.
• [24] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [25] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] 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.
• [28] 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.
• [29] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.