Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6NTBAA)

• DOT Name: Lysophosphatidylcholine acyltransferase 2 (LPCAT2)
• Synonyms: LPC acyltransferase 2; LPCAT-2; LysoPC acyltransferase 2; EC 2.3.1.23; 1-acylglycerol-3-phosphate O-acyltransferase 11; 1-AGP acyltransferase 11; 1-AGPAT 11; EC 2.3.1.51; 1-acylglycerophosphocholine O-acyltransferase; 1-alkenylglycerophosphocholine O-acyltransferase; EC 2.3.1.25; 1-alkylglycerophosphocholine O-acetyltransferase; EC 2.3.1.67; Acetyl-CoA:lyso-platelet-activating factor acetyltransferase; Acetyl-CoA:lyso-PAF acetyltransferase; Lyso-PAF acetyltransferase; LysoPAFAT; Acyltransferase-like 1; Lysophosphatidic acid acyltransferase alpha; LPAAT-alpha
• Gene Name: LPCAT2
• Related Disease:
  Colorectal carcinoma
  Matthew-Wood syndrome
  Neuralgia
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate carcinoma
• UniProt ID: PCAT2_HUMAN
• EC Number: 2.3.1.23; 2.3.1.25; 2.3.1.51; 2.3.1.67
• Pfam ID: PF01553 ; PF13202 ; PF13499
• Sequence:
  MSRCAQAAEVAATVPGAGVGNVGLRPPMVPRQASFFPPPVPNPFVQQTQIGSARRVQIVL
  LGIILLPIRVLLVALILLLAWPFAAISTVCCPEKLTHPITGWRRKITQTALKFLGRAMFF
  SMGFIVAVKGKIASPLEAPVFVAAPHSTFFDGIACVVAGLPSMVSRNENAQVPLIGRLLR
  AVQPVLVSRVDPDSRKNTINEIIKRTTSGGEWPQILVFPEGTCTNRSCLITFKPGAFIPG
  VPVQPVLLRYPNKLDTVTWTWQGYTFIQLCMLTFCQLFTKVEVEFMPVQVPNDEEKNDPV
  LFANKVRNLMAEALGIPVTDHTYEDCRLMISAGQLTLPMEAGLVEFTKISRKLKLDWDGV
  RKHLDEYASIASSSKGGRIGIEEFAKYLKLPVSDVLRQLFALFDRNHDGSIDFREYVIGL
  AVLCNPSNTEEIIQVAFKLFDVDEDGYITEEEFSTILQASLGVPDLDVSGLFKEIAQGDS
  ISYEEFKSFALKHPEYAKIFTTYLDLQTCHVFSLPKEVQTTPSTASNKVSPEKHEESTSD
  KKDD
• Function: Exhibits both acyltransferase and acetyltransferase activities. Catalyzes the conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC). Catalyzes the conversion 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone. Involved in platelet-activating factor (PAF) biosynthesis by catalyzing the conversion of the PAF precursor, 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) into 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF). Also converts lyso-PAF to 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine (PC), a major component of cell membranes and a PAF precursor. Under resting conditions, acyltransferase activity is preferred. Upon acute inflammatory stimulus, acetyltransferase activity is enhanced and PAF synthesis increases. Involved in the regulation of lipid droplet number and size.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[2]
Neuralgia	DISWO58J	Strong	Biomarker	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Limited	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[15]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[19]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Lysophosphatidylcholine acyltransferase 2 (LPCAT2).	[20]

References

• [1] Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance.Nat Commun. 2018 Jan 22;9(1):322. doi: 10.1038/s41467-017-02732-5.
• [2] Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148a on gene regulation.Cancer Sci. 2018 Jun;109(6):2013-2026. doi: 10.1111/cas.13610. Epub 2018 May 22.
• [3] Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop.FASEB J. 2017 Jul;31(7):2973-2980. doi: 10.1096/fj.201601183R. Epub 2017 Mar 24.
• [4] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [5] A systems genetics approach identifies CXCL14, ITGAX, and LPCAT2 as novel aggressive prostate cancer susceptibility genes.PLoS Genet. 2014 Nov 20;10(11):e1004809. doi: 10.1371/journal.pgen.1004809. eCollection 2014 Nov.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] 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.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] 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.
• [15] 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.
• [16] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [20] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.