Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIWM4GT)

• DOT Name: Retinol-binding protein 3 (RBP3)
• Synonyms: Interphotoreceptor retinoid-binding protein; IRBP; Interstitial retinol-binding protein
• Gene Name: RBP3
• Related Disease:
  Diabetic retinopathy
  Hyperglycemia
  Type-1/2 diabetes
  Brain neoplasm
  Head-neck squamous cell carcinoma
  Inherited retinal dystrophy
  Juvenile idiopathic arthritis
  Medullary thyroid gland carcinoma
  Multiple endocrine neoplasia type 2A
  Neoplasm
  Non-proliferative diabetic retinopathy
  Pheochromocytoma
  Retinitis pigmentosa 66
  Retinoblastoma
  Retinopathy
  Uveitis
  X-linked reticulate pigmentary disorder
  Autoimmune disease
  Hirschsprung disease
  Retinitis pigmentosa
  Leber congenital amaurosis 1
  Posterior uveitis
• UniProt ID: RET3_HUMAN
• Pfam ID: PF03572 ; PF11918
• Sequence:
  MMREWVLLMSVLLCGLAGPTHLFQPSLVLDMAKVLLDNYCFPENLLGMQEAIQQAIKSHE
  ILSISDPQTLASVLTAGVQSSLNDPRLVISYEPSTPEPPPQVPALTSLSEEELLAWLQRG
  LRHEVLEGNVGYLRVDSVPGQEVLSMMGEFLVAHVWGNLMGTSALVLDLRHCTGGQVSGI
  PYIISYLHPGNTILHVDTIYNRPSNTTTEIWTLPQVLGERYGADKDVVVLTSSQTRGVAE
  DIAHILKQMRRAIVVGERTGGGALDLRKLRIGESDFFFTVPVSRSLGPLGGGSQTWEGSG
  VLPCVGTPAEQALEKALAILTLRSALPGVVHCLQEVLKDYYTLVDRVPTLLQHLASMDFS
  TVVSEEDLVTKLNAGLQAASEDPRLLVRAIGPTETPSWPAPDAAAEDSPGVAPELPEDEA
  IRQALVDSVFQVSVLPGNVGYLRFDSFADASVLGVLAPYVLRQVWEPLQDTEHLIMDLRH
  NPGGPSSAVPLLLSYFQGPEAGPVHLFTTYDRRTNITQEHFSHMELPGPRYSTQRGVYLL
  TSHRTATAAEEFAFLMQSLGWATLVGEITAGNLLHTRTVPLLDTPEGSLALTVPVLTFID
  NHGEAWLGGGVVPDAIVLAEEALDKAQEVLEFHQSLGALVEGTGHLLEAHYARPEVVGQT
  SALLRAKLAQGAYRTAVDLESLASQLTADLQEVSGDHRLLVFHSPGELVVEEAPPPPPAV
  PSPEELTYLIEALFKTEVLPGQLGYLRFDAMAELETVKAVGPQLVRLVWQQLVDTAALVI
  DLRYNPGSYSTAIPLLCSYFFEAEPRQHLYSVFDRATSKVTEVWTLPQVAGQRYGSHKDL
  YILMSHTSGSAAEAFAHTMQDLQRATVIGEPTAGGALSVGIYQVGSSPLYASMPTQMAMS
  ATTGKAWDLAGVEPDITVPMSEALSIAQDIVALRAKVPTVLQTAGKLVADNYASAELGAK
  MATKLSGLQSRYSRVTSEVALAEILGADLQMLSGDPHLKAAHIPENAKDRIPGIVPMQIP
  SPEVFEELIKFSFHTNVLEDNIGYLRFDMFGDGELLTQVSRLLVEHIWKKIMHTDAMIID
  MRFNIGGPTSSIPILCSYFFDEGPPVLLDKIYSRPDDSVSELWTHAQVVGERYGSKKSMV
  ILTSSVTAGTAEEFTYIMKRLGRALVIGEVTSGGCQPPQTYHVDDTNLYLTIPTARSVGA
  SDGSSWEGVGVTPHVVVPAEEALARAKEMLQHNQLRVKRSPGLQDHL
• Function: IRBP shuttles 11-cis and all trans retinoids between the retinol isomerase in the pigment epithelium and the visual pigments in the photoreceptor cells of the retina.
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  The retinoid cycle in cones (daylight vision) (R-HSA-2187335)
• BioCyc Pathway: MetaCyc:ENSG00000107618-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
Diabetic retinopathy	DISHGUJM	Definitive	Altered Expression	[1]
Hyperglycemia	DIS0BZB5	Definitive	Altered Expression	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[1]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[3]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[4]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[5]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[6]
Multiple endocrine neoplasia type 2A	DIS7D3W2	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-proliferative diabetic retinopathy	DISPMG3Z	Strong	Genetic Variation	[9]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[6]
Retinitis pigmentosa 66	DISVKPIL	Strong	Autosomal recessive	[10]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[9]
Retinopathy	DISB4B0F	Strong	Biomarker	[9]
Uveitis	DISV0RYS	Strong	Biomarker	[11]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Biomarker	[9]
Autoimmune disease	DISORMTM	moderate	Biomarker	[12]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[13]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[14]
Leber congenital amaurosis 1	DISY2B33	Limited	Altered Expression	[15]
Posterior uveitis	DISIBJSM	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Retinol-binding protein 3 (RBP3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinol-binding protein 3 (RBP3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Retinol-binding protein 3 (RBP3).	[18]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Retinol-binding protein 3 (RBP3).	[19]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Retinol-binding protein 3 (RBP3).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
MG-132	DMKA2YS	Preclinical	MG-132 decreases the degradation of Retinol-binding protein 3 (RBP3).	[22]

References

• [1] Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy.Sci Transl Med. 2019 Jul 3;11(499):eaau6627. doi: 10.1126/scitranslmed.aau6627.
• [2] Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter.J Cell Biol. 1992 Dec;119(6):1681-7. doi: 10.1083/jcb.119.6.1681.
• [3] Insulin-like growth factor binding protein-3 suppresses vascular endothelial growth factor expression and tumor angiogenesis in head and neck squamous cell carcinoma.Cancer Sci. 2012 Jul;103(7):1259-66. doi: 10.1111/j.1349-7006.2012.02301.x. Epub 2012 May 25.
• [4] Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.Ophthalmology. 2016 May;123(5):1143-50. doi: 10.1016/j.ophtha.2016.01.009. Epub 2016 Feb 9.
• [5] Cellular immune responses of patients with juvenile chronic arthritis to retinal antigens and their synthetic peptides.Immunol Res. 1996;15(1):74-83. doi: 10.1007/BF02918285.
• [6] The mutation for medullary thyroid carcinoma with parathyroid tumors (MTC with PTs) is closely linked to the centromeric region of chromosome 10.Am J Hum Genet. 1990 Dec;47(6):946-51.
• [7] Genomic and yeast artificial chromosome long-range physical maps linking six loci in 10q11.2 and spanning the multiple endocrine neoplasia type 2A (MEN2A) region.Genomics. 1993 Sep;17(3):611-7. doi: 10.1006/geno.1993.1380.
• [8] Retinoblastoma: messenger RNA for interphotoreceptor retinoid binding protein.Curr Eye Res. 1992 May;11(5):425-33. doi: 10.3109/02713689209001796.
• [9] Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic retinopathy.Diabetologia. 2009 Dec;52(12):2633-41. doi: 10.1007/s00125-009-1548-8. Epub 2009 Oct 13.
• [10] A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1864-72. doi: 10.1167/iovs.08-2497. Epub 2008 Dec 13.
• [11] Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells.J Neuroinflammation. 2018 Feb 21;15(1):54. doi: 10.1186/s12974-018-1088-6.
• [12] Posttranslational modification of differentially expressed mitochondrial proteins in the retina during early experimental autoimmune uveitis.Mol Vis. 2011;17:1814-21. Epub 2011 Jul 6.
• [13] Deleted and normal chromosome 10 homologs from a patient with Hirschsprung disease isolated in two cell hybrids through enrichment by immunomagnetic selection.Cytogenet Cell Genet. 1993;63(2):102-6. doi: 10.1159/000133510.
• [14] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [15] Overexpression of Type 3 Iodothyronine Deiodinase Reduces Cone Death in the Leber Congenital Amaurosis Model Mice.Adv Exp Med Biol. 2018;1074:125-131. doi: 10.1007/978-3-319-75402-4_16.
• [16] Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism.Clin Exp Immunol. 2017 Dec;190(3):293-303. doi: 10.1111/cei.13021. Epub 2017 Aug 30.
• [17] 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.
• [18] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [21] 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.
• [22] Secretory defect and cytotoxicity: the potential disease mechanisms for the retinitis pigmentosa (RP)-associated interphotoreceptor retinoid-binding protein (IRBP). J Biol Chem. 2013 Apr 19;288(16):11395-406. doi: 10.1074/jbc.M112.418251. Epub 2013 Mar 13.