Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTENU47T)

• DOT Name: Acyl-protein thioesterase 1 (LYPLA1)
• Synonyms: APT-1; hAPT1; EC 3.1.2.-; Lysophospholipase 1; Lysophospholipase I; LPL-I; LysoPLA I; Palmitoyl-protein hydrolase; EC 3.1.2.22
• Gene Name: LYPLA1
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Metastatic melanoma
  Non-insulin dependent diabetes
  Type-1/2 diabetes
  Autoimmune lymphoproliferative syndrome type 1
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic tumour
  Prostate carcinoma
  Carcinoma
  HER2/NEU overexpressing breast cancer
  Advanced cancer
  Melanoma
• UniProt ID: LYPA1_HUMAN
• PDB ID: 1FJ2; 5SYM; 6QGN; 6QGO; 6QGQ; 6QGS
• EC Number: 3.1.2.-; 3.1.2.22
• Pfam ID: PF02230
• Sequence:
  MCGNNMSTPLPAIVPAARKATAAVIFLHGLGDTGHGWAEAFAGIRSSHIKYICPHAPVRP
  VTLNMNVAMPSWFDIIGLSPDSQEDESGIKQAAENIKALIDQEVKNGIPSNRIILGGFSQ
  GGALSLYTALTTQQKLAGVTALSCWLPLRASFPQGPIGGANRDISILQCHGDCDPLVPLM
  FGSLTVEKLKTLVNPANVTFKTYEGMMHSSCQQEMMDVKQFIDKLLPPID
• Function: Acts as an acyl-protein thioesterase. Hydrolyzes fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins or HRAS. Acts as a palmitoyl thioesterase that catalyzes depalmitoylation of proteins, such as ADRB2, KCNMA1 and SQSTM1. Acts as a negative regulator of autophagy by mediating palmitoylation of SQSTM1, decreasing affinity between SQSTM1 and ATG8 proteins and recruitment of ubiquitinated cargo proteins to autophagosomes. Acts as a lysophospholipase and hydrolyzes lysophosphatidylcholine (lyso-PC). Also hydrolyzes lysophosphatidylethanolamine (lyso-PE), lysophosphatidylinositol (lyso-PI) and lysophosphatidylserine (lyso-PS). Has much higher thioesterase activity than lysophospholipase activity. Contributes to the production of lysophosphatidic acid (LPA) during blood coagulation by recognizing and cleaving plasma phospholipids to generate lysophospholipids which in turn act as substrates for ENPP2 to produce LPA.
• Tissue Specificity: Platelets.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  RAS processing (R-HSA-9648002)
  eNOS activation (R-HSA-203615)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Biomarker	[1]
Atherosclerosis	DISMN9J3	Definitive	Biomarker	[1]
Metastatic melanoma	DISSL43L	Definitive	Altered Expression	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Definitive	Genetic Variation	[1]
Autoimmune lymphoproliferative syndrome type 1	DISAFGRA	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Carcinoma	DISH9F1N	moderate	Biomarker	[8]
HER2/NEU overexpressing breast cancer	DISYKID5	moderate	Biomarker	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Melanoma	DIS1RRCY	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[16]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Acyl-protein thioesterase 1 (LYPLA1).	[20]

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 Acyl-protein thioesterase 1 (LYPLA1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Acyl-protein thioesterase 1 (LYPLA1).	[18]

References

• [1] Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice.J Lipid Res. 2002 Jun;43(6):872-7.
• [2] Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior.Elife. 2018 Apr 12;7:e34362. doi: 10.7554/eLife.34362.
• [3] miR-29 contributes to normal endothelial function and can restore it in cardiometabolic disorders.EMBO Mol Med. 2018 Mar;10(3):e8046. doi: 10.15252/emmm.201708046.
• [4] Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.Am J Hum Genet. 1999 Apr;64(4):1002-14. doi: 10.1086/302333.
• [5] Inhibition of cell proliferation and migration in nonsmall cell lung cancer cells through the suppression of LYPLA1.Oncol Rep. 2019 Feb;41(2):973-980. doi: 10.3892/or.2018.6857. Epub 2018 Nov 9.
• [6] Adenoviral production of interleukin-2 at the tumor site removes the need for systemic postconditioning in adoptive cell therapy.Int J Cancer. 2017 Oct 1;141(7):1458-1468. doi: 10.1002/ijc.30839. Epub 2017 Jun 29.
• [7] Hypermethylation of the tumor necrosis factor receptor superfamily 6 (APT1, Fas, CD95/Apo-1) gene promoter at rel/nuclear factor kappaB sites in prostatic carcinoma.Mol Carcinog. 2001 Sep;32(1):36-43. doi: 10.1002/mc.1062.
• [8] Selection of DNA aptamers for extra cellular domain of human epidermal growth factor receptor 2 to detect HER2 positive carcinomas.Clin Transl Oncol. 2017 Aug;19(8):976-988. doi: 10.1007/s12094-017-1629-y. Epub 2017 Feb 21.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] 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.
• [15] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [16] 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.
• [17] Identification of potential biomarkers for predicting acute dermal irritation by proteomic analysis. J Appl Toxicol. 2011 Nov;31(8):762-72.
• [18] 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.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.