Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOKWR6C)

• DOT Name: E3 ubiquitin-protein ligase LRSAM1 (LRSAM1)
• Synonyms: EC 2.3.2.27; Leucine-rich repeat and sterile alpha motif-containing protein 1; RING-type E3 ubiquitin transferase LRSAM1; Tsg101-associated ligase; hTAL
• Gene Name: LRSAM1
• Related Disease:
  Charcot-Marie-Tooth disease axonal type 2P
  Advanced cancer
  Alzheimer disease
  Brain disease
  Charcot-Marie-Tooth disease type 1
  Charcot-Marie-Tooth disease type 1A
  Charcot-Marie-Tooth disease type 1B
  Charcot-Marie-Tooth disease type 2
  Chronic kidney disease
  Hepatocellular carcinoma
  Hirschsprung disease
  Kidney failure
  leukaemia
  Leukemia
  Nephropathy
  Scrub typhus
  T-cell leukaemia
  Charcot-Marie-Tooth disease type 3
  Hereditary motor and sensory neuropathy
  Multi-drug resistant tuberculosis
  Neuroblastoma
  Sickle-cell anaemia
  T-cell acute lymphoblastic leukaemia
• UniProt ID: LRSM1_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13855 ; PF07647 ; PF13920
• Sequence:
  MPLFFRKRKPSEEARKRLEYQMCLAKEAGADDILDISKCELSEIPFGAFATCKVLQKKVL
  IVHTNHLTSLLPKSCSLLSLATIKVLDLHDNQLTALPDDLGQLTALQVLNVERNQLMQLP
  RSIGNLTQLQTLNVKDNKLKELPDTVGELRSLRTLNISGNEIQRLPQMLAHVRTLEMLSL
  DASAMVYPPREVCGAGTAAILQFLCKESGLEYYPPSQYLLPILEQDGIENSRDSPDGPTD
  RFSREELEWQNRFSDYEKRKEQKMLEKLEFERRLELGQREHTQLLQQSSSQKDEILQTVK
  EEQSRLEQGLSEHQRHLNAERQRLQEQLKQTEQNISSRIQKLLQDNQRQKKSSEILKSLE
  NERIRMEQLMSITQEETESLRRRDVASAMQQMLTESCKNRLIQMAYESQRQNLVQQACSS
  MAEMDERFQQILSWQQMDQNKAISQILQESAMQKAAFEALQVKKDLMHRQIRSQIKLIET
  ELLQLTQLELKRKSLDTESLQEMISEQRWALSSLLQQLLKEKQQREEELREILTELEAKS
  ETRQENYWLIQYQRLLNQKPLSLKLQEEGMERQLVALLEELSAEHYLPIFAHHRLSLDLL
  SQMSPGDLAKVGVSEAGLQHEILRRVQELLDAARIQPELKPPMGEVVTPTAPQEPPESVR
  PSAPPAELEVQASECVVCLEREAQMIFLNCGHVCCCQQCCQPLRTCPLCRQDIAQRLRIY
  HSS
• Function: E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos. Bacterial recognition protein that defends the cytoplasm from invasive pathogens. Localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal leading to autophagy-mediated intracellular bacteria degradation (xenophagy).
• Tissue Specificity: Highly expressed in adult spinal cord motoneurons as well as in fetal spinal cord and muscle tissue.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease axonal type 2P	DISXRLFO	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Brain disease	DIS6ZC3X	Strong	Biomarker	[4]
Charcot-Marie-Tooth disease type 1	DIS56F9A	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 1A	DISSRZG7	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 1B	DISJRS1V	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Biomarker	[5]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Hirschsprung disease	DISUUSM1	Strong	Altered Expression	[8]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[9]
leukaemia	DISS7D1V	Strong	Genetic Variation	[10]
Leukemia	DISNAKFL	Strong	Genetic Variation	[10]
Nephropathy	DISXWP4P	Strong	Biomarker	[11]
Scrub typhus	DISRXONX	Strong	Genetic Variation	[12]
T-cell leukaemia	DISJ6YIF	Strong	Genetic Variation	[13]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Limited	Biomarker	[14]
Hereditary motor and sensory neuropathy	DISR0X2K	Limited	Biomarker	[14]
Multi-drug resistant tuberculosis	DIS1A2CS	Limited	Biomarker	[15]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[16]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[17]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase LRSAM1 (LRSAM1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase LRSAM1 (LRSAM1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase LRSAM1 (LRSAM1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase LRSAM1 (LRSAM1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase LRSAM1 (LRSAM1).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase LRSAM1 (LRSAM1).	[22]

References

• [1] 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.
• [2] Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951.Blood. 2004 Jan 15;103(2):442-50. doi: 10.1182/blood-2003-05-1495. Epub 2003 Sep 22.
• [3] Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1.Ann Neurol. 2016 Dec;80(6):823-833. doi: 10.1002/ana.24775. Epub 2016 Sep 30.
• [4] LRSAM1 E3 ubiquitin ligase: molecular neurobiological perspectives linked with brain diseases.Cell Mol Life Sci. 2019 Jun;76(11):2093-2110. doi: 10.1007/s00018-019-03055-y. Epub 2019 Mar 2.
• [5] Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease. PLoS Genet. 2010 Aug 26;6(8):e1001081. doi: 10.1371/journal.pgen.1001081.
• [6] Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?.Molecules. 2019 Feb 1;24(3):530. doi: 10.3390/molecules24030530.
• [7] Leucine-rich repeat and sterile alpha motif containing 1 promotes the oncogenic growth of human hepatocellular carcinoma cells.Cancer Cell Int. 2019 Oct 3;19:255. doi: 10.1186/s12935-019-0976-x. eCollection 2019.
• [8] Downregulation of microRNA-431-5p promotes enteric neural crest cell proliferation via targeting LRSAM1 in Hirschsprung's disease.Dev Growth Differ. 2019 May;61(4):294-302. doi: 10.1111/dgd.12606. Epub 2019 Apr 29.
• [9] Impact of polymyxin-B-associated acute kidney injury in 1-year mortality and renal function recovery.Int J Antimicrob Agents. 2018 Jul;52(1):86-89. doi: 10.1016/j.ijantimicag.2018.02.016. Epub 2018 Mar 2.
• [10] The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia.Haematologica. 2012 Sep;97(9):1405-13. doi: 10.3324/haematol.2011.059030. Epub 2012 Apr 4.
• [11] Acute kidney injury after pediatric cardiac surgery.Pediatr Neonatol. 2019 Feb;60(1):3-11. doi: 10.1016/j.pedneo.2018.03.007. Epub 2018 Mar 30.
• [12] Incidence, risk factors and clinical outcomes of acute kidney injury associated with scrub typhus: a retrospective study of 510 consecutive patients in South Korea (2001-2013).BMJ Open. 2017 Mar 15;7(3):e013882. doi: 10.1136/bmjopen-2016-013882.
• [13] The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein.EMBO J. 1990 Feb;9(2):415-24. doi: 10.1002/j.1460-2075.1990.tb08126.x.
• [14] Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease.Dis Model Mech. 2013 May;6(3):780-92. doi: 10.1242/dmm.010942. Epub 2013 Mar 8.
• [15] Rates and risk factors for nephrotoxicity and ototoxicity among tuberculosis patients in Tbilisi, Georgia.Int J Tuberc Lung Dis. 2019 Sep 1;23(9):1005-1011. doi: 10.5588/ijtld.18.0626.
• [16] LRSAM1 Depletion Affects Neuroblastoma SH-SY5Y Cell Growth and Morphology: The LRSAM1 c.2047-1G>A Loss-of-Function Variant Fails to Rescue The Phenotype.Cell J. 2018 Oct;20(3):340-347. doi: 10.22074/cellj.2018.5352. Epub 2018 May 15.
• [17] Optimized TAL effector nucleases (TALENs) for use in treatment of sickle cell disease.Mol Biosyst. 2012 Apr;8(4):1255-63. doi: 10.1039/c2mb05461b. Epub 2012 Feb 3.
• [18] Genetic rearrangements in relation to immunophenotype and outcome in T-cell acute lymphoblastic leukaemia.Best Pract Res Clin Haematol. 2010 Sep;23(3):307-18. doi: 10.1016/j.beha.2010.08.002. Epub 2010 Oct 30.
• [19] 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.
• [20] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [21] 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.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] 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.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.