Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9V1T5W)

• DOT Name: Calcium-independent phospholipase A2-gamma (PNPLA8)
• Synonyms: EC 3.1.1.-; EC 3.1.1.5; Intracellular membrane-associated calcium-independent phospholipase A2 gamma; iPLA2-gamma; PNPLA-gamma; Patatin-like phospholipase domain-containing protein 8; iPLA2-2
• Gene Name: PNPLA8
• Related Disease:
  Mitochondrial disease
  Mitochondrial myopathy-lactic acidosis-deafness syndrome
  Adenocarcinoma
  Colorectal carcinoma
  Prediabetes syndrome
• UniProt ID: PLPL8_HUMAN
• EC Number: 3.1.1.-; 3.1.1.5
• Pfam ID: PF01734
• Sequence:
  MSINLTVDIYIYLLSNARSVCGKQRSKQLYFLFSPKHYWRISHISLQRGFHTNIIRCKWT
  KSEAHSCSKHCYSPSNHGLHIGILKLSTSAPKGLTKVNICMSRIKSTLNSVSKAVFGNQN
  EMISRLAQFKPSSQILRKVSDSGWLKQKNIKQAIKSLKKYSDKSAEKSPFPEEKSHIIDK
  EEDIGKRSLFHYTSSITTKFGDSFYFLSNHINSYFKRKEKMSQQKENEHFRDKSELEDKK
  VEEGKLRSPDPGILAYKPGSESVHTVDKPTSPSAIPDVLQVSTKQSIANFLSRPTEGVQA
  LVGGYIGGLVPKLKYDSKSQSEEQEEPAKTDQAVSKDRNAEEKKRLSLQREKIIARVSID
  NRTRALVQALRRTTDPKLCITRVEELTFHLLEFPEGKGVAVKERIIPYLLRLRQIKDETL
  QAAVREILALIGYVDPVKGRGIRILSIDGGGTRGVVALQTLRKLVELTQKPVHQLFDYIC
  GVSTGAILAFMLGLFHMPLDECEELYRKLGSDVFSQNVIVGTVKMSWSHAFYDSQTWENI
  LKDRMGSALMIETARNPTCPKVAAVSTIVNRGITPKAFVFRNYGHFPGINSHYLGGCQYK
  MWQAIRASSAAPGYFAEYALGNDLHQDGGLLLNNPSALAMHECKCLWPDVPLECIVSLGT
  GRYESDVRNTVTYTSLKTKLSNVINSATDTEEVHIMLDGLLPPDTYFRFNPVMCENIPLD
  ESRNEKLDQLQLEGLKYIERNEQKMKKVAKILSQEKTTLQKINDWIKLKTDMYEGLPFFS
  KL
• Function: Calcium-independent and membrane-bound phospholipase, that catalyzes the esterolytic cleavage of fatty acids from glycerophospholipids to yield free fatty acids and lysophospholipids, hence regulating membrane physical properties and the release of lipid second messengers and growth factors. Hydrolyzes phosphatidylethanolamine, phosphatidylcholine and probably phosphatidylinositol with a possible preference for the former. Has also a broad substrate specificity in terms of fatty acid moieties, hydrolyzing saturated and mono-unsaturated fatty acids at nearly equal rates from either the sn-1 or sn-2 position in diacyl phosphatidylcholine. However, has a weak activity toward polyunsaturated fatty acids at the sn-2 position, and thereby favors the production of 2-arachidonoyl lysophosphatidylcholine, a key branch point metabolite in eicosanoid signaling. On the other hand, can produce arachidonic acid from the sn-1 position of diacyl phospholipid and from the sn-2 position of arachidonate-containing plasmalogen substrates. Therefore, plays an important role in the mobilization of arachidonic acid in response to cellular stimuli and the generation of lipid second messengers. Can also hydrolyze lysophosphatidylcholine. In the mitochondrial compartment, catalyzes the hydrolysis and release of oxidized aliphatic chains from cardiolipin and integrates mitochondrial bioenergetics and signaling. It is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.
• Tissue Specificity: Expressed in parenchymal tissues including heart, skeletal muscle, placenta, brain, liver and pancreas. Also expressed in bronchial epithelial cells and kidney. Highest expression is observed in skeletal muscle and heart.
• Reactome Pathway:
  Acyl chain remodelling of PE (R-HSA-1482839)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[1]
Mitochondrial myopathy-lactic acidosis-deafness syndrome	DISLXPUE	Strong	Autosomal recessive	[2]
Adenocarcinoma	DIS3IHTY	moderate	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[3]
Prediabetes syndrome	DISH2I53	Limited	Altered Expression	[4]

16 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 Calcium-independent phospholipase A2-gamma (PNPLA8).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[19]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Calcium-independent phospholipase A2-gamma (PNPLA8).	[20]

References

• [1] A neurodegenerative mitochondrial disease phenotype due to biallelic loss-of-function variants in PNPLA8 encoding calcium-independent phospholipase A2.Am J Med Genet A. 2018 May;176(5):1232-1237. doi: 10.1002/ajmg.a.38687.
• [2] Genetic ablation of calcium-independent phospholipase A2{gamma} leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J Biol Chem. 2009 Dec 18;284(51):35632-44. doi: 10.1074/jbc.M109.055194.
• [3] Group VIB Ca2+-independent phospholipase A2gamma promotes cellular membrane hydrolysis and prostaglandin production in a manner distinct from other intracellular phospholipases A2.J Biol Chem. 2005 Apr 8;280(14):14028-41. doi: 10.1074/jbc.M413766200. Epub 2005 Feb 4.
• [4] Fatty Acid-Stimulated Insulin Secretion vs. Lipotoxicity.Molecules. 2018 Jun 19;23(6):1483. doi: 10.3390/molecules23061483.
• [5] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [6] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [15] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [16] 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.
• [17] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.