Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8F2DCV)

• DOT Name: Lysophospholipase-like protein 1 (LYPLAL1)
• Synonyms: EC 3.1.2.22
• Gene Name: LYPLAL1
• Related Disease:
  Non-insulin dependent diabetes
  Myopia
  Non-alcoholic fatty liver disease
  Obesity
  High blood pressure
  Fatty liver disease
• UniProt ID: LYPL1_HUMAN
• PDB ID: 3U0V; 5KRE
• EC Number: 3.1.2.22
• Pfam ID: PF02230
• Sequence:
  MAAASGSVLQRCIVSPAGRHSASLIFLHGSGDSGQGLRMWIKQVLNQDLTFQHIKIIYPT
  APPRSYTPMKGGISNVWFDRFKITNDCPEHLESIDVMCQVLTDLIDEEVKSGIKKNRILI
  GGFSMGGCMAIHLAYRNHQDVAGVFALSSFLNKASAVYQALQKSNGVLPELFQCHGTADE
  LVLHSWAEETNSMLKSLGVTTKFHSFPNVYHELSKTELDILKLWILTKLPGEMEKQK
• Function: Palmitoyl thioesterase that catalyzes depalmitoylation of CGAS and KCNMA1. Acts as a regulator of innate immunity by mediating depalmitoylation of CGAS, thereby preventing CGAS homodimerization and cyclic GMP-AMP synthase activity. Does not exhibit phospholipase nor triacylglycerol lipase activity, able to hydrolyze only short chain substrates due to its shallow active site.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Myopia	DISK5S60	Strong	Altered Expression	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[4]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[5]
Fatty liver disease	DIS485QZ	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Lysophospholipase-like protein 1 (LYPLAL1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Lysophospholipase-like protein 1 (LYPLAL1).	[16]

References

• [1] Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes.Nat Commun. 2018 Jan 22;9(1):321. doi: 10.1038/s41467-017-02380-9.
• [2] Genetic variants on chromosome 1q41 influence ocular axial length and high myopia.PLoS Genet. 2012;8(6):e1002753. doi: 10.1371/journal.pgen.1002753. Epub 2012 Jun 7.
• [3] Genetic polymorphisms associated with nonalcoholic fatty liver disease in Uyghur population: a case-control study and meta-analysis.Lipids Health Dis. 2019 Jan 15;18(1):14. doi: 10.1186/s12944-018-0877-3.
• [4] Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits.Cell Metab. 2019 Apr 2;29(4):932-949.e4. doi: 10.1016/j.cmet.2018.12.013. Epub 2019 Jan 10.
• [5] Two obesity susceptibility loci in LYPLAL1 and ETV5 independently associated with childhood hypertension in Chinese population.Gene. 2017 Sep 5;627:284-289. doi: 10.1016/j.gene.2017.06.030. Epub 2017 Jun 20.
• [6] NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects.Hum Mol Genet. 2018 Jun 15;27(12):2214-2223. doi: 10.1093/hmg/ddy124.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.