Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB7CJKY)

• DOT Name: Lecithin retinol acyltransferase (LRAT)
• Synonyms: EC 2.3.1.135; Phosphatidylcholine--retinol O-acyltransferase
• Gene Name: LRAT
• Related Disease:
  Hepatocellular carcinoma
  Leber congenital amaurosis 14
  Neoplasm
  Alzheimer disease
  Cutaneous melanoma
  Inherited retinal dystrophy
  Leber congenital amaurosis 1
  Leber congenital amaurosis 9
  Leber hereditary optic neuropathy
  Night blindness
  Retinitis punctata albescens
  Retinopathy
  Urinary bladder neoplasm
  Vitamin A deficiency
  Melanoma
  Leber congenital amaurosis
  Retinitis pigmentosa
  Severe early-childhood-onset retinal dystrophy
  Blindness
  Coeliac disease
  Rheumatoid arthritis
• UniProt ID: LRAT_HUMAN
• EC Number: 2.3.1.135
• Pfam ID: PF04970
• Sequence:
  MKNPMLEVVSLLLEKLLLISNFTLFSSGAAGEDKGRNSFYETSSFHRGDVLEVPRTHLTH
  YGIYLGDNRVAHMMPDILLALTDDMGRTQKVVSNKRLILGVIVKVASIRVDTVEDFAYGA
  NILVNHLDESLQKKALLNEEVARRAEKLLGFTPYSLLWNNCEHFVTYCRYGTPISPQSDK
  FCETVKIIIRDQRSVLASAVLGLASIVCTGLVSYTTLPAIFIPFFLWMAG
• Function: Transfers the acyl group from the sn-1 position of phosphatidylcholine to all-trans retinol, producing all-trans retinyl esters. Retinyl esters are storage forms of vitamin A (Probable). LRAT plays a critical role in vision (Probable). It provides the all-trans retinyl ester substrates for the isomerohydrolase which processes the esters into 11-cis-retinol in the retinal pigment epithelium; due to a membrane-associated alcohol dehydrogenase, 11 cis-retinol is oxidized and converted into 11-cis-retinaldehyde which is the chromophore for rhodopsin and the cone photopigments (Probable). Required for the survival of cone photoreceptors and correct rod photoreceptor cell morphology.
• Tissue Specificity: Hepatic stellate cells and endothelial cells (at protein level). Found at high levels in testis and liver, followed by retinal pigment epithelium, small intestine, prostate, pancreas and colon. Low expression observed in brain. In fetal tissues, expressed in retinal pigment epithelium and liver, and barely in the brain.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
  Vitamin digestion and absorption (hsa04977)
• Reactome Pathway:
  The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
  Retinoid metabolism and transport (R-HSA-975634)
  Retinoid cycle disease events (R-HSA-2453864)
• BioCyc Pathway: MetaCyc:HS04474-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Leber congenital amaurosis 14	DISOJMRP	Definitive	Autosomal recessive	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[5]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[6]
Leber congenital amaurosis 1	DISY2B33	Strong	Genetic Variation	[6]
Leber congenital amaurosis 9	DIS35YGW	Strong	Autosomal recessive	[2]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Biomarker	[7]
Night blindness	DIS335K9	Strong	Genetic Variation	[8]
Retinitis punctata albescens	DISVJAI4	Strong	Genetic Variation	[9]
Retinopathy	DISB4B0F	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[10]
Vitamin A deficiency	DISBEPZO	Strong	Biomarker	[11]
Melanoma	DIS1RRCY	moderate	Altered Expression	[12]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[7]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[13]
Severe early-childhood-onset retinal dystrophy	DISFDRFO	Supportive	Autosomal recessive	[14]
Blindness	DISTIM10	Limited	Genetic Variation	[15]
Coeliac disease	DISIY60C	Limited	Biomarker	[16]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[17]

9 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 Lecithin retinol acyltransferase (LRAT).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lecithin retinol acyltransferase (LRAT).	[19]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Lecithin retinol acyltransferase (LRAT).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Lecithin retinol acyltransferase (LRAT).	[21]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Lecithin retinol acyltransferase (LRAT).	[22]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Lecithin retinol acyltransferase (LRAT).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lecithin retinol acyltransferase (LRAT).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Lecithin retinol acyltransferase (LRAT).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lecithin retinol acyltransferase (LRAT).	[26]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Platelet-derived growth factor receptor in hepatocellular carcinoma is a prognostic marker independent of underlying liver cirrhosis.Oncotarget. 2017 Jun 13;8(24):39534-39546. doi: 10.18632/oncotarget.17134.
• [4] Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.Nat Genet. 2011 May;43(5):436-41. doi: 10.1038/ng.801. Epub 2011 Apr 3.
• [5] Human melanomas of fibroblast and epithelial morphology differ widely in their ability to synthesize retinyl esters.Carcinogenesis. 2002 Nov;23(11):1821-30. doi: 10.1093/carcin/23.11.1821.
• [6] Pathophysilogical mechanism and treatment strategies for Leber congenital amaurosis.Adv Exp Med Biol. 2014;801:791-6. doi: 10.1007/978-1-4614-3209-8_99.
• [7] Screening genes of the retinoid metabolism: novel LRAT mutation in leber congenital amaurosis. Am J Ophthalmol. 2006 Oct;142(4):702-4. doi: 10.1016/j.ajo.2006.04.057.
• [8] Comparison between the enzymatic activity, structure and substrate binding of mouse and human lecithin retinol acyltransferase.Biochem Biophys Res Commun. 2019 Nov 19;519(4):832-837. doi: 10.1016/j.bbrc.2019.09.061. Epub 2019 Sep 24.
• [9] A homozygous frameshift mutation in LRAT causes retinitis punctata albescens.Ophthalmology. 2012 Sep;119(9):1899-906. doi: 10.1016/j.ophtha.2012.02.037. Epub 2012 May 3.
• [10] Reduced lecithin: retinol acyltransferase expression correlates with increased pathologic tumor stage in bladder cancer.Clin Cancer Res. 2004 May 15;10(10):3429-37. doi: 10.1158/1078-0432.CCR-03-0756.
• [11] Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency.J Biol Chem. 2005 Dec 2;280(48):40226-34. doi: 10.1074/jbc.M509643200. Epub 2005 Sep 20.
• [12] Knockdown of lecithin retinol acyltransferase increases all-trans retinoic acid levels and restores retinoid sensitivity in malignant melanoma cells.Exp Dermatol. 2014 Nov;23(11):832-7. doi: 10.1111/exd.12548. Epub 2014 Oct 10.
• [13] Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays. Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5690-8. doi: 10.1167/iovs.07-0610.
• [14] Early onset retinal dystrophy due to mutations in LRAT: molecular analysis and detailed phenotypic study. Invest Ophthalmol Vis Sci. 2012 Jun 22;53(7):3927-38. doi: 10.1167/iovs.12-9548.
• [15] Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial.Lancet. 2014 Oct 25;384(9953):1513-20. doi: 10.1016/S0140-6736(14)60153-7. Epub 2014 Jul 13.
• [16] Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies.Cell Mol Life Sci. 2018 Dec;75(23):4385-4401. doi: 10.1007/s00018-018-2898-5. Epub 2018 Aug 10.
• [17] Retinoic acid receptors and GATA transcription factors activate the transcription of the human lecithin:retinol acyltransferase gene.Int J Biochem Cell Biol. 2009 Mar;41(3):546-53. doi: 10.1016/j.biocel.2008.06.007. Epub 2008 Jul 4.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] 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.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [22] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [23] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [26] 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.