Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK1C2KL)

• DOT Name: Phosphatidate phosphatase LPIN3 (LPIN3)
• Synonyms: EC 3.1.3.4; Lipin-3; Lipin-3-like
• Gene Name: LPIN3
• Related Disease: Non-small-cell lung cancer
• UniProt ID: LPIN3_HUMAN
• EC Number: 3.1.3.4
• Pfam ID: PF16876 ; PF04571 ; PF08235
• Sequence:
  MNYVGQLAETVFGTVKELYRGLNPATLSGGIDVLVVKQVDGSFRCSPFHVRFGKLGVLRS
  REKVVDIELNGEPVDLHMKLGDSGEAFFVQELESDDEHVPPGLCTSPIPWGGLSGFPSDS
  QLGTASEPEGLVMAGTASTGRRKRRRRRKPKQKEDAVATDSSPEELEAGAESELSLPEKL
  RPEPPGVQLEEKSSLQPKDIYPYSDGEWPPQASLSAGELTSPKSDSELEVRTPEPSPLRA
  ESHMQWAWGRLPKVARAERPESSVVLEGRAGATSPPRGGPSTPSTSVAGGVDPLGLPIQQ
  TEAGADLQPDTEDPTLVGPPLHTPETEESKTQSSGDMGLPPASKSWSWATLEVPVPTGQP
  ERVSRGKGSPKRSQHLGPSDIYLDDLPSLDSENAALYFPQSDSGLGARRWSEPSSQKSLR
  DPNPEHEPEPTLDTVDTIALSLCGGLADSRDISLEKFNQHSVSYQDLTKNPGLLDDPNLV
  VKINGKHYNWAVAAPMILSLQAFQKNLPKSTMDKLEREKMPRKGGRWWFSWRRRDFLAEE
  RSAQKEKTAAKEQQGEKTEVLSSDDDAPDSPVILEIPSLPPSTPPSTPTYKKSLRLSSDQ
  IRRLNLQEGANDVVFSVTTQYQGTCRCKATIYLWKWDDKVVISDIDGTITKSDALGHILP
  QLGKDWTHQGITSLYHKIQLNGYKFLYCSARAIGMADLTKGYLQWVSEGGCSLPKGPILL
  SPSSLFSALHREVIEKKPEVFKVACLSDIQQLFLPHGQPFYAAFGNRPNDVFAYRQVGLP
  ESRIFTVNPRGELIQELIKNHKSTYERLGEVVELLFPPVARGPSTDLANPEYSNFCYWRE
  PLPAVDLDTLD
• Function: Magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis therefore regulates fatty acid metabolism.
• Tissue Specificity: Significant expression in intestine and other regions of the gastrointestinal tract.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Glycerophospholipid metabolism (hsa00564)
  Metabolic pathways (hsa01100)
  mTOR sig.ling pathway (hsa04150)
  Alcoholic liver disease (hsa04936)
• Reactome Pathway:
  Synthesis of PE (R-HSA-1483213)
  Depolymerization of the Nuclear Lamina (R-HSA-4419969)
  Triglyceride biosynthesis (R-HSA-75109)
  Synthesis of PC (R-HSA-1483191)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Phosphatidate phosphatase LPIN3 (LPIN3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phosphatidate phosphatase LPIN3 (LPIN3).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Phosphatidate phosphatase LPIN3 (LPIN3).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Phosphatidate phosphatase LPIN3 (LPIN3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[5]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[9]
Oleic acid	DM54O1Z	Investigative	Oleic acid decreases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[11]
Farnesol	DMV2X1B	Investigative	Farnesol decreases the expression of Phosphatidate phosphatase LPIN3 (LPIN3).	[11]

References

• [1] The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer.Ann Oncol. 2015 Dec;26(12):2464-9. doi: 10.1093/annonc/mdv394. Epub 2015 Sep 25.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.
• [10] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [11] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.