Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYE92QY)

• DOT Name: Lysosome-associated membrane glycoprotein 1 (LAMP1)
• Synonyms: LAMP-1; Lysosome-associated membrane protein 1; CD107 antigen-like family member A; CD antigen CD107a
• Gene Name: LAMP1
• UniProt ID: LAMP1_HUMAN
• PDB ID: 8ATH; 8FY5; 8FYF
• Pfam ID: PF01299 ; PF21222
• Sequence:
  MAAPGSARRPLLLLLLLLLLGLMHCASAAMFMVKNGNGTACIMANFSAAFSVNYDTKSGP
  KNMTFDLPSDATVVLNRSSCGKENTSDPSLVIAFGRGHTLTLNFTRNATRYSVQLMSFVY
  NLSDTHLFPNASSKEIKTVESITDIRADIDKKYRCVSGTQVHMNNVTVTLHDATIQAYLS
  NSSFSRGETRCEQDRPSPTTAPPAPPSPSPSPVPKSPSVDKYNVSGTNGTCLLASMGLQL
  NLTYERKDNTTVTRLLNINPNKTSASGSCGAHLVTLELHSEGTTVLLFQFGMNASSSRFF
  LQGIQLNTILPDARDPAFKAANGSLRALQATVGNSYKCNAEEHVRVTKAFSVNIFKVWVQ
  AFKVEGGQFGSVEECLLDENSMLIPIAVGGALAGLVLIVLIAYLVGRKRSHAGYQTI
• Function: Lysosomal membrane glycoprotein which plays an important role in lysosome biogenesis, lysosomal pH regulation, autophagy and cholesterol homeostasis. Acts as an important regulator of lysosomal lumen pH regulation by acting as a direct inhibitor of the proton channel TMEM175, facilitating lysosomal acidification for optimal hydrolase activity. Also plays an important role in NK-cells cytotoxicity. Mechanistically, participates in cytotoxic granule movement to the cell surface and perforin trafficking to the lytic granule. In addition, protects NK-cells from degranulation-associated damage induced by their own cytotoxic granule content. Presents carbohydrate ligands to selectins ; (Microbial infection) Acts as a receptor for Lassa virus glycoprotein. Promotes also fusion of the virus with host membrane in less acidic endosomes ; (Microbial infection) Supports the FURIN-mediated cleavage of mumps virus fusion protein F by interacting with both FURIN and the unprocessed form but not the processed form of the viral protein F.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Tuberculosis (hsa05152)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Lysosome-associated membrane glycoprotein 1 (LAMP1) increases the Liver injury ADR of Methotrexate.	[26]

2 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 Lysosome-associated membrane glycoprotein 1 (LAMP1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[11]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[12]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[10]
Imatinib	DM7RJXL	Approved	Imatinib increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[9]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[14]
GDC0941	DM1YAK6	Phase 2	GDC0941 increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[4]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[21]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[22]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal increases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[23]
Lead acetate	DML0GZ2	Investigative	Lead acetate decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[24]
Biotin	DMKMCE1	Investigative	Biotin decreases the expression of Lysosome-associated membrane glycoprotein 1 (LAMP1).	[25]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] 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.
• [4] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Arsenic trioxide induces autophagic cell death in osteosarcoma cells via the ROS-TFEB signaling pathway. Biochem Biophys Res Commun. 2018 Jan 29;496(1):167-175. doi: 10.1016/j.bbrc.2018.01.018. Epub 2018 Jan 4.
• [8] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [11] Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells. Exp Cell Res. 2011 Jun 10;317(10):1397-410. doi: 10.1016/j.yexcr.2011.02.014. Epub 2011 Mar 3.
• [12] Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy. Cell Biol Toxicol. 2023 Jun;39(3):729-749. doi: 10.1007/s10565-021-09635-8. Epub 2021 Aug 17.
• [13] Imatinib disturbs lysosomal function and morphology and impairs the activity of mTORC1 in human hepatocyte cell lines. Food Chem Toxicol. 2022 Apr;162:112869. doi: 10.1016/j.fct.2022.112869. Epub 2022 Feb 16.
• [14] Targeting the Enterohepatic Bile Acid Signaling Induces Hepatic Autophagy via a CYP7A1-AKT-mTOR Axis in Mice. Cell Mol Gastroenterol Hepatol. 2016 Oct 22;3(2):245-260. doi: 10.1016/j.jcmgh.2016.10.002. eCollection 2017 Mar.
• [15] GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell death. Cancer Lett. 2013 Feb 1;329(1):27-36. doi: 10.1016/j.canlet.2012.09.007. Epub 2012 Sep 18.
• [16] 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.
• [17] 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.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [22] Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. Free Radic Biol Med. 2012 Nov 1;53(9):1760-9. doi: 10.1016/j.freeradbiomed.2012.08.591. Epub 2012 Sep 1.
• [23] Upregulation of the TFEB-mediated lysosome function relieves 4-Hydroxynonenal-Induced apoptosis. Chem Biol Interact. 2022 Aug 1;362:109963. doi: 10.1016/j.cbi.2022.109963. Epub 2022 May 9.
• [24] SIRT1/mTOR pathway-mediated autophagy dysregulation promotes Pb-induced hepatic lipid accumulation in HepG2 cells. Environ Toxicol. 2022 Mar;37(3):549-563. doi: 10.1002/tox.23420. Epub 2021 Nov 29.
• [25] Clusters of biotin-responsive genes in human peripheral blood mononuclear cells. J Nutr Biochem. 2004 Jul;15(7):433-9.
• [26] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.