Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT03UIYC)

• DOT Name: Acyl-protein thioesterase 2 (LYPLA2)
• Synonyms: APT-2; EC 3.1.2.-; Lysophospholipase II; LPL-II; LysoPLA II; Palmitoyl-protein hydrolase; EC 3.1.2.22
• Gene Name: LYPLA2
• Related Disease:
  Hyperlipidemia, familial combined, LPL related
  Melanoma
• UniProt ID: LYPA2_HUMAN
• PDB ID: 5SYN; 6BJE
• EC Number: 3.1.2.-; 3.1.2.22
• Pfam ID: PF02230
• Sequence:
  MCGNTMSVPLLTDAATVSGAERETAAVIFLHGLGDTGHSWADALSTIRLPHVKYICPHAP
  RIPVTLNMKMVMPSWFDLMGLSPDAPEDEAGIKKAAENIKALIEHEMKNGIPANRIVLGG
  FSQGGALSLYTALTCPHPLAGIVALSCWLPLHRAFPQAANGSAKDLAILQCHGELDPMVP
  VRFGALTAEKLRSVVTPARVQFKTYPGVMHSSCPQEMAAVKEFLEKLLPPV
• Function: Acts as an acyl-protein thioesterase hydrolyzing fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins, GAP43, ZDHHC6 or HRAS. Deacylates GAP43. Mediates depalmitoylation of ZDHHC6. Has lysophospholipase activity. Hydrolyzes prostaglandin glycerol esters (PG-Gs) in the following order prostaglandin D2-glycerol ester (PGD2-G) > prostaglandin E2 glycerol ester (PGE2-G) > prostaglandin F2-alpha-glycerol ester (PGF2-alpha-G). Hydrolyzes 1-arachidonoylglycerol but not 2-arachidonoylglycerol or arachidonoylethanolamide.
• Tissue Specificity: Expressed in various breast cancer cell lines.
• KEGG Pathway: Glycerophospholipid metabolism (hsa00564)
• Reactome Pathway: L1CAM interactions (R-HSA-373760)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Altered Expression	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[2]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PGF2alpha	DM4XAU7	Clinical trial	Acyl-protein thioesterase 2 (LYPLA2) increases the hydrolysis of PGF2alpha.	[10]
PGD2	DMYDW6J	Investigative	Acyl-protein thioesterase 2 (LYPLA2) increases the hydrolysis of PGD2.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Acyl-protein thioesterase 2 (LYPLA2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acyl-protein thioesterase 2 (LYPLA2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acyl-protein thioesterase 2 (LYPLA2).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Acyl-protein thioesterase 2 (LYPLA2).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Acyl-protein thioesterase 2 (LYPLA2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Acyl-protein thioesterase 2 (LYPLA2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Acyl-protein thioesterase 2 (LYPLA2).	[9]

References

• [1] Differential gene expression of blood-derived cell lines in familial combined hyperlipidemia.Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2149-54. doi: 10.1161/01.ATV.0000145978.70872.63. Epub 2004 Sep 23.
• [2] Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads.Nat Commun. 2019 Feb 20;10(1):877. doi: 10.1038/s41467-019-08691-3.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] 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.
• [9] 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.
• [10] Identification of the major prostaglandin glycerol ester hydrolase in human cancer cells. J Biol Chem. 2014 Dec 5;289(49):33741-53. doi: 10.1074/jbc.M114.582353. Epub 2014 Oct 9.