Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWI96P4)

• DOT Name: Lysophospholipid acyltransferase 5 (LPCAT3)
• Synonyms: LPLAT 5; EC 2.3.1.-; 1-acylglycerophosphocholine O-acyltransferase; EC 2.3.1.23; 1-acylglycerophosphoethanolamine O-acyltransferase; EC 2.3.1.n7; 1-acylglycerophosphoserine O-acyltransferase; EC 2.3.1.n6; Lysophosphatidylcholine acyltransferase; LPCAT; Lyso-PC acyltransferase; Lysophosphatidylcholine acyltransferase 3; Lyso-PC acyltransferase 3; Lysophosphatidylserine acyltransferase; LPSAT; Lyso-PS acyltransferase; Membrane-bound O-acyltransferase domain-containing protein 5; O-acyltransferase domain-containing protein 5
• Gene Name: LPCAT3
• Related Disease:
  Beta-thalassemia major
  Hepatocellular carcinoma
  Neoplasm
  Vascular disease
  Coronary atherosclerosis
  Coronary heart disease
  Arteriosclerosis
  Asthma
  Atherosclerosis
  Essential hypertension
  Hyperglycemia
  Non-alcoholic steatohepatitis
  Sickle-cell anaemia
• UniProt ID: MBOA5_HUMAN
• EC Number: 2.3.1.-; 2.3.1.23; 2.3.1.n6; 2.3.1.n7
• Pfam ID: PF03062
• Sequence:
  MASSAEGDEGTVVALAGVLQSGFQELSLNKLATSLGASEQALRLIISIFLGYPFALFYRH
  YLFYKETYLIHLFHTFTGLSIAYFNFGNQLYHSLLCIVLQFLILRLMGRTITAVLTTFCF
  QMAYLLAGYYYTATGNYDIKWTMPHCVLTLKLIGLAVDYFDGGKDQNSLSSEQQKYAIRG
  VPSLLEVAGFSYFYGAFLVGPQFSMNHYMKLVQGELIDIPGKIPNSIIPALKRLSLGLFY
  LVGYTLLSPHITEDYLLTEDYDNHPFWFRCMYMLIWGKFVLYKYVTCWLVTEGVCILTGL
  GFNGFEEKGKAKWDACANMKVWLFETNPRFTGTIASFNINTNAWVARYIFKRLKFLGNKE
  LSQGLSLLFLALWHGLHSGYLVCFQMEFLIVIVERQAARLIQESPTLSKLAAITVLQPFY
  YLVQQTIHWLFMGYSMTAFCLFTWDKWLKVYKSIYFLGHIFFLSLLFILPYIHKAMVPRK
  EKLKKME
• Function: Lysophospholipid O-acyltransferase (LPLAT) that catalyzes the reacylation step of the phospholipid remodeling process also known as the Lands cycle. Catalyzes transfer of the fatty acyl chain from fatty acyl-CoA to 1-acyl lysophospholipid to form various classes of phospholipids. Converts 1-acyl lysophosphatidylcholine (LPC) into phosphatidylcholine (PC) (LPCAT activity), 1-acyl lysophosphatidylserine (LPS) into phosphatidylserine (PS) (LPSAT activity) and 1-acyl lysophosphatidylethanolamine (LPE) into phosphatidylethanolamine (PE) (LPEAT activity). Favors polyunsaturated fatty acyl-CoAs as acyl donors compared to saturated fatty acyl-CoAs. Has higher activity for LPC acyl acceptors compared to LPEs and LPSs. Can also transfer the fatty acyl chain from fatty acyl-CoA to 1-O-alkyl lysophospholipid or 1-O-alkenyl lysophospholipid with lower efficiency. Acts as a major LPC O-acyltransferase in liver and intestine. As a component of the liver X receptor/NR1H3 or NR1H2 signaling pathway, mainly catalyzes the incorporation of arachidonate into PCs of endoplasmic reticulum (ER) membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles. Promotes processing of sterol regulatory protein SREBF1 in hepatocytes, likely by facilitating the translocation of SREBF1-SCAP complex from ER to the Golgi apparatus. Participates in mechanisms by which the liver X receptor/NR1H3 or NR1H2 signaling pathway counteracts lipid-induced ER stress response and inflammation. Down-regulates hepatic inflammation by limiting arachidonic acid availability for synthesis of inflammatory eicosanoids, such as prostaglandins. In enterocytes, acts as a component of a gut-brain feedback loop that coordinates dietary lipid absorption and food intake. Regulates the abundance of PCs containing linoleate and arachidonate in enterocyte membranes, enabling passive diffusion of fatty acids and cholesterol across the membrane for efficient chylomicron assembly. In the intestinal crypt, acts as a component of dietary-responsive phospholipid-cholesterol axis, regulating the biosynthesis of cholesterol and its mitogenic effects on intestinal stem cells.
• Tissue Specificity: Highly expressed in liver, pancreas and adipose tissue. Very low expression in skeletal muscle and heart. Detected in neutrophils.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ferroptosis (hsa04216)
• Reactome Pathway:
  Acyl chain remodelling of PS (R-HSA-1482801)
  Acyl chain remodelling of PE (R-HSA-1482839)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Beta-thalassemia major	DISW06BV	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Vascular disease	DISVS67S	Strong	Biomarker	[4]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[5]
Coronary heart disease	DIS5OIP1	moderate	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[6]
Asthma	DISW9QNS	Limited	Genetic Variation	[7]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[6]
Essential hypertension	DIS7WI98	Limited	Genetic Variation	[8]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[9]
Non-alcoholic steatohepatitis	DIST4788	Limited	Biomarker	[10]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[18]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[20]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Lysophospholipid acyltransferase 5 (LPCAT3).	[23]

References

• [1] C3 polymorphism in beta-thalassemia.Acta Haematol. 1984;71(1):45-8. doi: 10.1159/000206507.
• [2] Lysophosphatidylcholine acyltransferase 1 altered phospholipid composition and regulated hepatoma progression.J Hepatol. 2013 Aug;59(2):292-9. doi: 10.1016/j.jhep.2013.02.030. Epub 2013 Apr 6.
• [3] Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis.Cell Stem Cell. 2018 Feb 1;22(2):206-220.e4. doi: 10.1016/j.stem.2017.12.017.
• [4] Association between the C3F gene and atherosclerotic vascular diseases.Hum Hered. 1975;25(4):279-83. doi: 10.1159/000152736.
• [5] Association between coronary heart disease and the C3F-gene in essential hypertension.Circulation. 1978 Oct;58(4):622-5. doi: 10.1161/01.cir.58.4.622.
• [6] A novel assay for measuring recombinant human lysophosphatidylcholine acyltransferase 3 activity.FEBS Open Bio. 2019 Oct;9(10):1734-1743. doi: 10.1002/2211-5463.12712. Epub 2019 Aug 30.
• [7] Association between C3 complement types and bronchial asthma.Hum Hered. 1985;35(4):263-4. doi: 10.1159/000153557.
• [8] Association between the C3F-gene and essential hypertension.Clin Sci (Lond). 1981 Dec;61 Suppl 7:363s-365s. doi: 10.1042/cs061363s.
• [9] Liver-specific overexpression of LPCAT3 reduces postprandial hyperglycemia and improves lipoprotein metabolic profile in mice.Nutr Diabetes. 2016 Apr 25;6(4):e206. doi: 10.1038/nutd.2016.12.
• [10] Caspase-independent hepatocyte death: A result of the decrease of lysophosphatidylcholine acyltransferase 3 in non-alcoholic steatohepatitis.J Gastroenterol Hepatol. 2019 Jul;34(7):1256-1262. doi: 10.1111/jgh.14461. Epub 2018 Sep 23.
• [11] Hypoxia-mediated impaired erythrocyte Lands' Cycle is pathogenic for sickle cell disease.Sci Rep. 2016 Jul 20;6:29637. doi: 10.1038/srep29637.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 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.
• [18] 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.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [20] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [21] 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.
• [22] 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.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.