Details of Drug Off-Target (DOT)

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

• DOT Name: Phosphatidate phosphatase LPIN2 (LPIN2)
• Synonyms: EC 3.1.3.4; Lipin-2
• Gene Name: LPIN2
• Related Disease:
  Crohn disease
  Rheumatoid arthritis
  Anemia
  Congenital dyserythropoietic anemia
  Familial Mediterranean fever
  Granular corneal dystrophy type II
  Hereditary periodic fever syndrome
  IRIDA syndrome
  Leukopenia
  Lipodystrophy
  Majeed syndrome
  Metabolic disorder
  Myopia
  Relapsing fever
  Trichohepatoenteric syndrome
  Asthma
  Inflammation
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Type-1/2 diabetes
  Chronic recurrent multifocal osteomyelitis
  Congenital generalized lipodystrophy
  Dorfman-Chanarin disease
  Generalized lipodystrophy
  Intestinal disorder
  Myopathy
  Non-insulin dependent diabetes
  Non-syndromic ichthyosis
  Obesity
• UniProt ID: LPIN2_HUMAN
• EC Number: 3.1.3.4
• Pfam ID: PF16876 ; PF04571 ; PF08235
• Sequence:
  MNYVGQLAGQVIVTVKELYKGINQATLSGCIDVIVVQQQDGSYQCSPFHVRFGKLGVLRS
  KEKVIDIEINGSAVDLHMKLGDNGEAFFVEETEEEYEKLPAYLATSPIPTEDQFFKDIDT
  PLVKSGGDETPSQSSDISHVLETETIFTPSSVKKKKRRRKKYKQDSKKEEQAASAAAEDT
  CDVGVSSDDDKGAQAARGSSNASLKEEECKEPLLFHSGDHYPLSDGDWSPLETTYPQTAC
  PKSDSELEVKPAESLLRSESHMEWTWGGFPESTKVSKRERSDHHPRTATITPSENTHFRV
  IPSEDNLISEVEKDASMEDTVCTIVKPKPRALGTQMSDPTSVAELLEPPLESTQISSMLD
  ADHLPNAALAEAPSESKPAAKVDSPSKKKGVHKRSQHQGPDDIYLDDLKGLEPEVAALYF
  PKSESEPGSRQWPESDTLSGSQSPQSVGSAAADSGTECLSDSAMDLPDVTLSLCGGLSEN
  GEISKEKFMEHIITYHEFAENPGLIDNPNLVIRIYNRYYNWALAAPMILSLQVFQKSLPK
  ATVESWVKDKMPKKSGRWWFWRKRESMTKQLPESKEGKSEAPPASDLPSSSKEPAGARPA
  ENDSSSDEGSQELEESITVDPIPTEPLSHGSTTSYKKSLRLSSDQIAKLKLHDGPNDVVF
  SITTQYQGTCRCAGTIYLWNWNDKIIISDIDGTITKSDALGQILPQLGKDWTHQGIAKLY
  HSINENGYKFLYCSARAIGMADMTRGYLHWVNDKGTILPRGPLMLSPSSLFSAFHREVIE
  KKPEKFKIECLNDIKNLFAPSKQPFYAAFGNRPNDVYAYTQVGVPDCRIFTVNPKGELIQ
  ERTKGNKSSYHRLSELVEHVFPLLSKEQNSAFPCPEFSSFCYWRDPIPEVDLDDLS
• Function: Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis in the reticulum endoplasmic membrane. Plays important roles in controlling the metabolism of fatty acids at different levels. Acts also as a nuclear transcriptional coactivator for PPARGC1A to modulate lipid metabolism.
• Tissue Specificity: Expressed in liver, lung, kidney, placenta, spleen, thymus, lymph node, prostate, testes, small intestine, and colon.
• 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

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[2]
Anemia	DISTVL0C	Strong	Altered Expression	[3]
Congenital dyserythropoietic anemia	DIS6FAT6	Strong	Biomarker	[4]
Familial Mediterranean fever	DISVP5WP	Strong	Genetic Variation	[5]
Granular corneal dystrophy type II	DISAEE20	Strong	Biomarker	[4]
Hereditary periodic fever syndrome	DISS9RWQ	Strong	Biomarker	[6]
IRIDA syndrome	DISPN8YW	Strong	Biomarker	[4]
Leukopenia	DISJMBMM	Strong	Genetic Variation	[7]
Lipodystrophy	DIS3SGVD	Strong	Biomarker	[8]
Majeed syndrome	DIS8AI2U	Strong	Autosomal recessive	[9]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[10]
Myopia	DISK5S60	Strong	Genetic Variation	[8]
Relapsing fever	DISEA4L7	Strong	Genetic Variation	[7]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[9]
Asthma	DISW9QNS	moderate	Genetic Variation	[11]
Inflammation	DISJUQ5T	moderate	Genetic Variation	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[13]
Prostate cancer	DISF190Y	moderate	Biomarker	[13]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[13]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[12]
Chronic recurrent multifocal osteomyelitis	DIST1OU2	Disputed	Biomarker	[14]
Congenital generalized lipodystrophy	DIS4XF8N	Limited	Genetic Variation	[15]
Dorfman-Chanarin disease	DISKKT3R	Limited	Biomarker	[15]
Generalized lipodystrophy	DISC6HI8	Limited	Genetic Variation	[15]
Intestinal disorder	DISGPMUQ	Limited	Biomarker	[15]
Myopathy	DISOWG27	Limited	Biomarker	[15]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[16]
Non-syndromic ichthyosis	DISZ9QBQ	Limited	Biomarker	[15]
Obesity	DIS47Y1K	Limited	Biomarker	[17]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Lovastatin	DM9OZWQ	Approved	Phosphatidate phosphatase LPIN2 (LPIN2) decreases the response to substance of Lovastatin.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[22]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphatidate phosphatase LPIN2 (LPIN2).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Phosphatidate phosphatase LPIN2 (LPIN2).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Phosphatidate phosphatase LPIN2 (LPIN2).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Phosphatidate phosphatase LPIN2 (LPIN2).	[27]

References

• [1] Genetic susceptibility factors in a cohort of 38 patients with SAPHO syndrome: a study of PSTPIP2, NOD2, and LPIN2 genes.J Rheumatol. 2010 Feb;37(2):401-9. doi: 10.3899/jrheum.090456. Epub 2009 Dec 23.
• [2] New genes associated with rheumatoid arthritis identified by gene expression profiling.Int J Immunogenet. 2017 Jun;44(3):107-113. doi: 10.1111/iji.12313. Epub 2017 Apr 2.
• [3] A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2.J Biol Chem. 2009 Oct 23;284(43):29968-78. doi: 10.1074/jbc.M109.023663. Epub 2009 Aug 28.
• [4] Efficacy of anti-IL-1 treatment in Majeed syndrome.Ann Rheum Dis. 2013 Mar;72(3):410-3. doi: 10.1136/annrheumdis-2012-201818. Epub 2012 Oct 20.
• [5] Clinical and genetic association, radiological findings and response to biological therapy in seven children from Qatar with non-bacterial osteomyelitis.Int J Rheum Dis. 2017 Sep;20(9):1286-1296. doi: 10.1111/1756-185X.12940. Epub 2016 Nov 9.
• [6] A splice site mutation confirms the role of LPIN2 in Majeed syndrome.Arthritis Rheum. 2007 Mar;56(3):960-4. doi: 10.1002/art.22431.
• [7] Compound heterozygous LPIN2 pathogenic variants in a patient with Majeed syndrome with recurrent fever and severe neutropenia: case report.BMC Med Genet. 2019 Nov 14;20(1):182. doi: 10.1186/s12881-019-0919-3.
• [8] Evaluation of Lipin 2 as a candidate gene for autosomal dominant 1 high-grade myopia.Gene. 2005 Jun 6;352:10-9. doi: 10.1016/j.gene.2005.02.019.
• [9] Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet. 2005 Jul;42(7):551-7. doi: 10.1136/jmg.2005.030759.
• [10] Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling.Prog Lipid Res. 2013 Jul;52(3):305-16. doi: 10.1016/j.plipres.2013.04.001. Epub 2013 Apr 17.
• [11] Genome-wide association study of body mass index in 23 000 individuals with and without asthma.Clin Exp Allergy. 2013 Apr;43(4):463-74. doi: 10.1111/cea.12054.
• [12] The lipin family: mutations and metabolism.Curr Opin Lipidol. 2009 Jun;20(3):165-70. doi: 10.1097/MOL.0b013e32832adee5.
• [13] Chromosomal structural variations during progression of a prostate epithelial cell line to a malignant metastatic state inactivate the NF2, NIPSNAP1, UGT2B17, and LPIN2 genes.Cancer Biol Ther. 2013 Sep;14(9):840-52. doi: 10.4161/cbt.25329. Epub 2013 Jul 26.
• [14] Chronic recurrent multifocal osteomyelitis: a concise review and genetic update.Clin Orthop Relat Res. 2007 Sep;462:11-9. doi: 10.1097/BLO.0b013e3180986d73.
• [15] Inborn errors of cytoplasmic triglyceride metabolism.J Inherit Metab Dis. 2015 Jan;38(1):85-98. doi: 10.1007/s10545-014-9767-7. Epub 2014 Oct 10.
• [16] LPIN2 is associated with type 2 diabetes, glucose metabolism, and body composition.Diabetes. 2007 Dec;56(12):3020-6. doi: 10.2337/db07-0338. Epub 2007 Sep 5.
• [17] Lipin-2 reduces proinflammatory signaling induced by saturated fatty acids in macrophages.J Biol Chem. 2012 Mar 30;287(14):10894-904. doi: 10.1074/jbc.M112.342915. Epub 2012 Feb 8.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [26] 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.
• [27] 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.
• [28] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin response in HCT-116 cells. PLoS One. 2011 Apr 4;6(4):e18306. doi: 10.1371/journal.pone.0018306.