Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ6TTYV)

• DOT Name: Phospholipase B1, membrane-associated (PLB1)
• Synonyms: Phospholipase B; hPLB; Lysophospholipase; EC 3.1.1.5; Phospholipase A2; EC 3.1.1.4; Phospholipase B/lipase; PLB/LIP; Triacylglycerol lipase; EC 3.1.1.3
• Gene Name: PLB1
• Related Disease:
  Escherichia coli infection
  Hyperglycemia
  Type-1/2 diabetes
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Chronic granulomatous disease
  Chronic obstructive pulmonary disease
  Colon carcinoma
  Colorectal carcinoma
  Coronary atherosclerosis
  Coronary heart disease
  Crohn disease
  Depression
  Glomerulonephritis
  Hepatocellular carcinoma
  Hutchinson-Gilford progeria syndrome
  Leukemia
  Lung cancer
  Lung carcinoma
  Narcolepsy
  Neuroblastoma
  Neurodegeneration with brain iron accumulation
  Non-small-cell lung cancer
  Parkinson disease
  Prostate carcinoma
  Rheumatoid arthritis
  Ulcerative colitis
  Nasal polyp
  Adult respiratory distress syndrome
  Colonic neoplasm
  Alzheimer disease
  Atopic dermatitis
  Cognitive impairment
  Mood disorder
  Myocardial infarction
  Neurodegeneration with brain iron accumulation 2A
  Pantothenate kinase-associated neurodegeneration
  Prostate cancer
• UniProt ID: PLB1_HUMAN
• EC Number: 3.1.1.3; 3.1.1.4; 3.1.1.5
• Pfam ID: PF00657
• Sequence:
  MGLRPGIFLLELLLLLGQGTPQIHTSPRKSTLEGQLWPETLKNSPFPCNPNKLGVNMPSK
  SVHSLKPSDIKFVAAIGNLEIPPDPGTGDLEKQDWTERPQQVCMGVMTVLSDIIRYFSPS
  VPMPVCHTGKRVIPHDGAEDLWIQAQELVRNMKENLQLDFQFDWKLINVFFSNASQCYLC
  PSAQQNGLAAGGVDELMGVLDYLQQEVPRAFVNLVDLSEVAEVSRQYHGTWLSPAPEPCN
  CSEETTRLAKVVMQWSYQEAWNSLLASSRYSEQESFTVVFQPFFYETTPSLHSEDPRLQD
  STTLAWHLWNRMMEPAGEKDEPLSVKHGRPMKCPSQESPYLFSYRNSNYLTRLQKPQDKL
  EVREGAEIRCPDKDPSDTVPTSVHRLKPADINVIGALGDSLTAGNGAGSTPGNVLDVLTQ
  YRGLSWSVGGDENIGTVTTLANILREFNPSLKGFSVGTGKETSPNAFLNQAVAGGRAEDL
  PVQARRLVDLMKNDTRIHFQEDWKIITLFIGGNDLCDFCNDLVHYSPQNFTDNIGKALDI
  LHAEVPRAFVNLVTVLEIVNLRELYQEKKVYCPRMILRSLCPCVLKFDDNSTELATLIEF
  NKKFQEKTHQLIESGRYDTREDFTVVVQPFFENVDMPKTSEGLPDNSFFAPDCFHFSSKS
  HSRAASALWNNMLEPVGQKTTRHKFENKINITCPNQVQPFLRTYKNSMQGHGTWLPCRDR
  APSALHPTSVHALRPADIQVVAALGDSLTAGNGIGSKPDDLPDVTTQYRGLSYSAGGDGS
  LENVTTLPNILREFNRNLTGYAVGTGDANDTNAFLNQAVPGAKAEDLMSQVQTLMQKMKD
  DHRVNFHEDWKVITVLIGGSDLCDYCTDSNLYSAANFVHHLRNALDVLHREVPRVLVNLV
  DFLNPTIMRQVFLGNPDKCPVQQASVLCNCVLTLRENSQELARLEAFSRAYRSSMRELVG
  SGRYDTQEDFSVVLQPFFQNIQLPVLADGLPDTSFFAPDCIHPNQKFHSQLARALWTNML
  EPLGSKTETLDLRAEMPITCPTQNEPFLRTPRNSNYTYPIKPAIENWGSDFLCTEWKASN
  SVPTSVHQLRPADIKVVAALGDSLTTAVGARPNNSSDLPTSWRGLSWSIGGDGNLETHTT
  LPNILKKFNPYLLGFSTSTWEGTAGLNVAAEGARARDMPAQAWDLVERMKNSPDINLEKD
  WKLVTLFIGVNDLCHYCENPEAHLATEYVQHIQQALDILSEELPRAFVNVVEVMELASLY
  QGQGGKCAMLAAQNNCTCLRHSQSSLEKQELKKVNWNLQHGISSFSYWHQYTQREDFAVV
  VQPFFQNTLTPLNERGDTDLTFFSEDCFHFSDRGHAEMAIALWNNMLEPVGRKTTSNNFT
  HSRAKLKCPSPESPYLYTLRNSRLLPDQAEEAPEVLYWAVPVAAGVGLVVGIIGTVVWRC
  RRGGRREDPPMSLRTVAL
• Function: Calcium-independent membrane-associated phospholipase that catalyzes complete diacylation of phospholipids by hydrolyzing both sn-1 and sn-2 fatty acyl chains attached to the glycerol backbone (phospholipase B activity). Has dual phospholipase and lysophospholipase activities toward diacylphospholipids. Preferentially cleaves sn-2 ester bonds over sn-1 bonds. Acts as a lipase toward glycerolipid substrates. Hydrolyzes fatty acyl chains of diacylglycerols with preference for the sn-2 position and of triacylglycerols with not positional selectivity. May also hydrolyze long chain retinyl esters such as retinyl palmitate. May contribute to digestion of dietary phospholipids, glycerolipids and retinoids, facilitating lipid absorption at the brush border.
• Tissue Specificity: Expressed in the epidermis (at protein level).
• 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)
  Vitamin digestion and absorption (hsa04977)
• Reactome Pathway:
  Retinoid metabolism and transport (R-HSA-975634)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Escherichia coli infection	DISPP65M	Definitive	Biomarker	[1]
Hyperglycemia	DIS0BZB5	Definitive	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Chronic granulomatous disease	DIS9ZR24	Strong	Genetic Variation	[7]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[11]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[11]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[12]
Depression	DIS3XJ69	Strong	Biomarker	[13]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Genetic Variation	[16]
Leukemia	DISNAKFL	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Biomarker	[18]
Lung carcinoma	DISTR26C	Strong	Biomarker	[18]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[19]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[20]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Biomarker	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[22]
Parkinson disease	DISQVHKL	Strong	Biomarker	[23]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[25]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[12]
Nasal polyp	DISLP3XE	moderate	Biomarker	[26]
Adult respiratory distress syndrome	DISIJV47	Disputed	Genetic Variation	[27]
Colonic neoplasm	DISSZ04P	Disputed	Altered Expression	[28]
Alzheimer disease	DISF8S70	Limited	Biomarker	[29]
Atopic dermatitis	DISTCP41	Limited	Biomarker	[30]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[31]
Mood disorder	DISLVMWO	Limited	Genetic Variation	[32]
Myocardial infarction	DIS655KI	Limited	Altered Expression	[33]
Neurodegeneration with brain iron accumulation 2A	DIS9XEBF	Limited	Genetic Variation	[34]
Pantothenate kinase-associated neurodegeneration	DIS50V55	Limited	Genetic Variation	[35]
Prostate cancer	DISF190Y	Limited	Biomarker	[24]

5 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 Phospholipase B1, membrane-associated (PLB1).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phospholipase B1, membrane-associated (PLB1).	[37]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phospholipase B1, membrane-associated (PLB1).	[38]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Phospholipase B1, membrane-associated (PLB1).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phospholipase B1, membrane-associated (PLB1).	[42]

2 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 Phospholipase B1, membrane-associated (PLB1).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phospholipase B1, membrane-associated (PLB1).	[41]

References

• [1] mRNA differential display of acute-phase proteins in experimental Escherichia coli infection.Electrophoresis. 2000 Aug;21(14):2957-68. doi: 10.1002/1522-2683(20000801)21:14<2957::AID-ELPS2957>3.0.CO;2-L.
• [2] 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.
• [3] Diabetes-induced oxidative stress is mediated by Ca2+-independent phospholipase A2 in neutrophils.J Immunol. 2010 Feb 1;184(3):1507-15. doi: 10.4049/jimmunol.0901219. Epub 2010 Jan 6.
• [4] Current insights into functions of phospholipase A2 receptor in normal and cancer cells: More questions than answers.Semin Cancer Biol. 2019 Jun;56:116-127. doi: 10.1016/j.semcancer.2017.11.002. Epub 2017 Nov 2.
• [5] Induction of dendritic cell-mediated T-cell activation by modified but not native low-density lipoprotein in humans and inhibition by annexin a5: involvement of heat shock proteins.Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):197-205. doi: 10.1161/ATVBAHA.114.304342. Epub 2014 Nov 13.
• [6] Plasma phospholipase A2 activity may serve as a novel diagnostic biomarker for the diagnosis of breast cancer.Oncol Lett. 2018 Apr;15(4):5236-5242. doi: 10.3892/ol.2018.7915. Epub 2018 Jan 31.
• [7] CRISPR/Cas9-generated p47(phox)-deficient cell line for Chronic Granulomatous Disease gene therapy vector development.Sci Rep. 2017 Mar 13;7:44187. doi: 10.1038/srep44187.
• [8] Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis.Respir Res. 2019 Apr 2;20(1):64. doi: 10.1186/s12931-019-1036-8.
• [9] Deficiency of phospholipase A2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc(Min/+) mice.Cancer Res. 2013 May 1;73(9):2806-16. doi: 10.1158/0008-5472.CAN-12-2374. Epub 2013 Jan 29.
• [10] Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer.Mod Pathol. 2005 Feb;18(2):212-20. doi: 10.1038/modpathol.3800284.
• [11] Exploring calcium ion-dependent effect on the intermolecular interaction between human secreted phospholipase A2 and its peptide inhibitors in coronary artery disease.J Mol Graph Model. 2019 Dec;93:107449. doi: 10.1016/j.jmgm.2019.107449. Epub 2019 Sep 7.
• [12] Genetic Variations at rs3129891 and rs77005575 are Associated With Reduced Expression of Enteric -defensins in IBD Patients.J Clin Gastroenterol. 2020 Jul;54(6):e50-e55. doi: 10.1097/MCG.0000000000001146.
• [13] Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.Biol Psychiatry. 2010 Mar 15;67(6):550-7. doi: 10.1016/j.biopsych.2009.11.005. Epub 2009 Dec 24.
• [14] Serum uromodulin-a marker of kidney function and renal parenchymal integrity.Nephrol Dial Transplant. 2018 Feb 1;33(2):284-295. doi: 10.1093/ndt/gfw422.
• [15] Platelet-activating factor in cirrhotic liver and hepatocellular carcinoma.World J Gastroenterol. 2006 May 7;12(17):2773-8. doi: 10.3748/wjg.v12.i17.2773.
• [16] The role of lipid metabolism in aging, lifespan regulation, and age-related disease.Aging Cell. 2019 Dec;18(6):e13048. doi: 10.1111/acel.13048. Epub 2019 Sep 27.
• [17] Naja nigricollis CMS-9 enhances the mitochondria-mediated death pathway in adaphostin-treated human leukaemia U937 cells.Clin Exp Pharmacol Physiol. 2011 Nov;38(11):755-63. doi: 10.1111/j.1440-1681.2011.05585.x.
• [18] Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells.Int J Oncol. 2014 Sep;45(3):978-84. doi: 10.3892/ijo.2014.2486. Epub 2014 Jun 10.
• [19] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [20] Taiwan cobra phospholipase A2 elicits posttranscriptional up-regulation of ADAM17 in human neuroblastoma SK-N-SH cells.J Cell Biochem. 2010 Sep 1;111(1):148-57. doi: 10.1002/jcb.22681.
• [21] A new PLA2G6 mutation in a family with infantile neuroaxonal dystrophy.J Neurol Sci. 2017 Oct 15;381:209-212. doi: 10.1016/j.jns.2017.08.3260. Epub 2017 Sep 1.
• [22] Exome-Wide Association Study Identifies Low-Frequency Coding Variants in 2p23.2 and 7p11.2 Associated with Survival of Non-Small Cell Lung Cancer Patients.J Thorac Oncol. 2017 Apr;12(4):644-656. doi: 10.1016/j.jtho.2016.12.025. Epub 2017 Jan 16.
• [23] Comparison of Administration Routes on the Protective Effects of Bee Venom Phospholipase A2 in a Mouse Model of Parkinson's Disease.Front Aging Neurosci. 2018 Jun 11;10:179. doi: 10.3389/fnagi.2018.00179. eCollection 2018.
• [24] Phospholipase A2-Responsive Phosphate Micelle-Loaded UCNPs for Bioimaging of Prostate Cancer Cells.Sci Rep. 2017 Nov 22;7(1):16073. doi: 10.1038/s41598-017-16136-4.
• [25] Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.PLoS One. 2014 Feb 10;9(2):e87645. doi: 10.1371/journal.pone.0087645. eCollection 2014.
• [26] Phospholipase A2-dependent release of inflammatory cytokines by superantigen-stimulated nasal polyps of patients with chronic rhinosinusitis.Am J Rhinol Allergy. 2015 Sep-Oct;29(5):e122-8. doi: 10.2500/ajra.2015.29.4224.
• [27] In silico investigation of the molecular effects caused by R123H variant in secretory phospholipase A2-IIA associated with ARDS.J Mol Graph Model. 2018 May;81:68-76. doi: 10.1016/j.jmgm.2018.02.014. Epub 2018 Mar 6.
• [28] Expression of secretory phospholipase A2 in colon tumor cells potentiates tumor growth.Mol Carcinog. 2007 Feb;46(2):106-16. doi: 10.1002/mc.20271.
• [29] Bee Venom Soluble Phospholipase A2 Exerts Neuroprotective Effects in a Lipopolysaccharide-Induced Mouse Model of Alzheimer's Disease via Inhibition of Nuclear Factor-Kappa B.Front Aging Neurosci. 2019 Nov 1;11:287. doi: 10.3389/fnagi.2019.00287. eCollection 2019.
• [30] Bee Venom Phospholipase A2 Alleviate House Dust Mite-Induced Atopic Dermatitis-Like Skin Lesions by the CD206 Mannose Receptor.Toxins (Basel). 2018 Apr 2;10(4):146. doi: 10.3390/toxins10040146.
• [31] Bee venom phospholipase A2 ameliorates Alzheimer's disease pathology in A vaccination treatment without inducing neuro-inflammation in a 3xTg-AD mouse model.Sci Rep. 2018 Nov 26;8(1):17369. doi: 10.1038/s41598-018-35030-1.
• [32] Genetic association between the phospholipase A2 gene and unipolar affective disorder: a multicentre case-control study.Psychiatr Genet. 2003 Dec;13(4):211-20. doi: 10.1097/00041444-200312000-00004.
• [33] Human myoblast transplantation in mice infarcted heart alters the expression profile of cardiac genes associated with left ventricle remodeling.Int J Cardiol. 2016 Jan 1;202:710-21. doi: 10.1016/j.ijcard.2015.09.115. Epub 2015 Oct 22.
• [34] Mitochondria from a mouse model of the human infantile neuroaxonal dystrophy (INAD) with genetic defects in VIA iPLA2 have disturbed Ca(2+) regulation with reduction in Ca(2+) capacity.Neurochem Int. 2016 Oct;99:187-193. doi: 10.1016/j.neuint.2016.07.002. Epub 2016 Jul 7.
• [35] Neurodegeneration with brain iron accumulation.Handb Clin Neurol. 2011;100:161-72. doi: 10.1016/B978-0-444-52014-2.00009-4.
• [36] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [37] 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.
• [38] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [39] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [40] 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.
• [41] 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.
• [42] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.