Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5FL0WU)

• DOT Name: 85/88 kDa calcium-independent phospholipase A2 (PLA2G6)
• Synonyms: CaI-PLA2; EC 3.1.1.4; 2-lysophosphatidylcholine acylhydrolase; EC 3.1.1.5; Group VI phospholipase A2; GVI PLA2; Intracellular membrane-associated calcium-independent phospholipase A2 beta; iPLA2-beta; Palmitoyl-CoA hydrolase; EC 3.1.2.2; Patatin-like phospholipase domain-containing protein 9; PNPLA9
• Gene Name: PLA2G6
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Neurodegeneration with brain iron accumulation 2A
  Neurodegeneration with brain iron accumulation 2B
  PLA2G6-associated neurodegeneration
  Acute coronary syndrome
  Autosomal recessive Parkinson disease 14
  Breast carcinoma
  Carcinoma
  Cerebellar ataxia
  Colorectal carcinoma
  Cutaneous melanoma
  Dementia
  Depression
  Hepatocellular carcinoma
  Hereditary spastic paraplegia
  Lung cancer
  Lung neoplasm
  Melanocytic nevus
  Membranous glomerulonephritis
  Nasopharyngeal carcinoma
  Nervous system disease
  Neurodegeneration with brain iron accumulation
  Non-insulin dependent diabetes
  Obesity
  Parkinson disease
  Parkinsonian disorder
  Pathologic nystagmus
  Prostate cancer
  Prostate carcinoma
  Psychotic disorder
  Schizophrenia
  Stroke
  Type-1/2 diabetes
  Ulcerative colitis
  Vascular purpura
  Young-onset Parkinson disease
  Advanced cancer
  Arterial thrombosis
  Familial adenomatous polyposis
  Lung carcinoma
  Pantothenate kinase-associated neurodegeneration
  Alzheimer disease
  Cardiovascular disease
  Dystonia
  Lewy body dementia
  Neuroaxonal dystrophy
  Neuroblastoma
  Neuroferritinopathy
• UniProt ID: PLPL9_HUMAN
• EC Number: 3.1.1.4; 3.1.1.5; 3.1.2.2
• Pfam ID: PF00023 ; PF12796 ; PF01734
• Sequence:
  MQFFGRLVNTFSGVTNLFSNPFRVKEVAVADYTSSDRVREEGQLILFQNTPNRTWDCVLV
  NPRNSQSGFRLFQLELEADALVNFHQYSSQLLPFYESSPQVLHTEVLQHLTDLIRNHPSW
  SVAHLAVELGIRECFHHSRIISCANCAENEEGCTPLHLACRKGDGEILVELVQYCHTQMD
  VTDYKGETVFHYAVQGDNSQVLQLLGRNAVAGLNQVNNQGLTPLHLACQLGKQEMVRVLL
  LCNARCNIMGPNGYPIHSAMKFSQKGCAEMIISMDSSQIHSKDPRYGASPLHWAKNAEMA
  RMLLKRGCNVNSTSSAGNTALHVAVMRNRFDCAIVLLTHGANADARGEHGNTPLHLAMSK
  DNVEMIKALIVFGAEVDTPNDFGETPTFLASKIGRLVTRKAILTLLRTVGAEYCFPPIHG
  VPAEQGSAAPHHPFSLERAQPPPISLNNLELQDLMHISRARKPAFILGSMRDEKRTHDHL
  LCLDGGGVKGLIIIQLLIAIEKASGVATKDLFDWVAGTSTGGILALAILHSKSMAYMRGM
  YFRMKDEVFRGSRPYESGPLEEFLKREFGEHTKMTDVRKPKVMLTGTLSDRQPAELHLFR
  NYDAPETVREPRFNQNVNLRPPAQPSDQLVWRAARSSGAAPTYFRPNGRFLDGGLLANNP
  TLDAMTEIHEYNQDLIRKGQANKVKKLSIVVSLGTGRSPQVPVTCVDVFRPSNPWELAKT
  VFGAKELGKMVVDCCTDPDGRAVDRARAWCEMVGIQYFRLNPQLGTDIMLDEVSDTVLVN
  ALWETEVYIYEHREEFQKLIQLLLSP
• Function: Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction. Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 or sn-2 position of phospholipids (phospholipase A1 and A2 activity respectively), producing lysophospholipids that are used in deacylation-reacylation cycles. Hydrolyzes both saturated and unsaturated long fatty acyl chains in various glycerophospholipid classes such as phosphatidylcholines, phosphatidylethanolamines and phosphatidates, with a preference for hydrolysis at sn-2 position. Can further hydrolyze lysophospholipids carrying saturated fatty acyl chains (lysophospholipase activity). Upon oxidative stress, contributes to remodeling of mitochondrial phospholipids in pancreatic beta cells, in a repair mechanism to reduce oxidized lipid content. Preferentially hydrolyzes oxidized polyunsaturated fatty acyl chains from cardiolipins, yielding monolysocardiolipins that can be reacylated with unoxidized fatty acyls to regenerate native cardiolipin species. Hydrolyzes oxidized glycerophosphoethanolamines present in pancreatic islets, releasing oxidized polyunsaturated fatty acids such as hydroxyeicosatetraenoates (HETEs). Has thioesterase activity toward fatty-acyl CoA releasing CoA-SH known to facilitate fatty acid transport and beta-oxidation in mitochondria particularly in skeletal muscle. Plays a role in regulation of membrane dynamics and homeostasis. Selectively hydrolyzes sn-2 arachidonoyl group in plasmalogen phospholipids, structural components of lipid rafts and myelin. Regulates F-actin polymerization at the pseudopods, which is required for both speed and directionality of MCP1/CCL2-induced monocyte chemotaxis. Targets membrane phospholipids to produce potent lipid signaling messengers. Generates lysophosphatidate (LPA, 1-acyl-glycerol-3-phosphate), which acts via G-protein receptors in various cell types. Has phospholipase A2 activity toward platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), likely playing a role in inactivation of this potent pro-inflammatory signaling lipid. In response to glucose, amplifies calcium influx in pancreatic beta cells to promote INS secretion; [Isoform Ankyrin-iPLA2-1]: Lacks the catalytic domain and may act as a negative regulator of the catalytically active isoforms; [Isoform Ankyrin-iPLA2-2]: Lacks the catalytic domain and may act as a negative regulator of the catalytically active isoforms.
• Tissue Specificity: Four different transcripts were found to be expressed in a distinct tissue distribution.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Arachidonic acid metabolism (hsa00590)
  Linoleic acid metabolism (hsa00591)
  alpha-Linolenic acid metabolism (hsa00592)
  Metabolic pathways (hsa01100)
  Ras sig.ling pathway (hsa04014)
  Efferocytosis (hsa04148)
  Vascular smooth muscle contraction (hsa04270)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway:
  Acyl chain remodeling of CL (R-HSA-1482798)
  Acyl chain remodelling of PE (R-HSA-1482839)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Altered Expression	[1]
Atherosclerosis	DISMN9J3	Definitive	Altered Expression	[1]
Neurodegeneration with brain iron accumulation 2A	DIS9XEBF	Definitive	Autosomal recessive	[2]
Neurodegeneration with brain iron accumulation 2B	DIST9P34	Definitive	Autosomal recessive	[3]
PLA2G6-associated neurodegeneration	DIS52D4D	Definitive	Autosomal recessive	[4]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[5]
Autosomal recessive Parkinson disease 14	DISYC4IP	Strong	Autosomal recessive	[6]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Carcinoma	DISH9F1N	Strong	Altered Expression	[8]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[10]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[11]
Dementia	DISXL1WY	Strong	Genetic Variation	[12]
Depression	DIS3XJ69	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[16]
Melanocytic nevus	DISYS32D	Strong	Biomarker	[17]
Membranous glomerulonephritis	DISFSUKQ	Strong	Biomarker	[18]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[19]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[20]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Genetic Variation	[21]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[22]
Obesity	DIS47Y1K	Strong	Altered Expression	[23]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[24]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[25]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[26]
Prostate cancer	DISF190Y	Strong	Altered Expression	[27]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[27]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[28]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[29]
Stroke	DISX6UHX	Strong	Genetic Variation	[30]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[31]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[8]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[15]
Young-onset Parkinson disease	DIS05LFS	Strong	Genetic Variation	[32]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[33]
Arterial thrombosis	DIS2LR4O	moderate	Biomarker	[34]
Familial adenomatous polyposis	DISW53RE	moderate	Genetic Variation	[35]
Lung carcinoma	DISTR26C	moderate	Biomarker	[36]
Pantothenate kinase-associated neurodegeneration	DIS50V55	moderate	Genetic Variation	[37]
Alzheimer disease	DISF8S70	Limited	Biomarker	[38]
Cardiovascular disease	DIS2IQDX	Limited	Altered Expression	[39]
Dystonia	DISJLFGW	Limited	Biomarker	[40]
Lewy body dementia	DISAE66J	Limited	Biomarker	[38]
Neuroaxonal dystrophy	DISHSV8Z	Limited	Genetic Variation	[41]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[42]
Neuroferritinopathy	DIS0E4F3	Limited	Biomarker	[43]

3 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 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[44]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[53]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[45]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[46]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[48]
Aspirin	DM672AH	Approved	Aspirin increases the expression of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[49]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[50]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[51]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[52]
bromoenol lactone	DMKQ0CA	Investigative	bromoenol lactone decreases the activity of 85/88 kDa calcium-independent phospholipase A2 (PLA2G6).	[54]

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