Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJI1XF3)

• DOT Name: N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD)
• Synonyms: N-acyl phosphatidylethanolamine phospholipase D; NAPE-PLD; NAPE-hydrolyzing phospholipase D; EC 3.1.4.54
• Gene Name: NAPEPLD
• UniProt ID: NAPEP_HUMAN
• PDB ID: 4QN9
• EC Number: 3.1.4.54
• Pfam ID: PF12706
• Sequence:
  MDENESNQSLMTSSQYPKEAVRKRQNSARNSGASDSSRFSRKSFKLDYRLEEDVTKSKKG
  KDGRFVNPWPTWKNPSIPNVLRWLIMEKDHSSVPSSKEELDKELPVLKPYFITNPEEAGV
  REAGLRVTWLGHATVMVEMDELIFLTDPIFSSRASPSQYMGPKRFRRSPCTISELPPIDA
  VLISHNHYDHLDYNSVIALNERFGNELRWFVPLGLLDWMQKCGCENVIELDWWEENCVPG
  HDKVTFVFTPSQHWCKRTLMDDNKVLWGSWSVLGPWNRFFFAGDTGYCPAFEEIGKRFGP
  FDLAAIPIGAYEPRWFMKYQHVDPEEAVRIHTDVQTKKSMAIHWGTFALANEHYLEPPVK
  LNEALERYGLNAEDFFVLKHGESRYLNNDDENF
• Function: D-type phospholipase that hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce bioactive N-acylethanolamines/fatty acid ethanolamides (NAEs/FAEs) and phosphatidic acid. Cleaves the terminal phosphodiester bond of diacyl- and alkenylacyl-NAPEs, primarily playing a role in the generation of long-chain saturated and monounsaturated NAEs in the brain. May control NAPE homeostasis in dopaminergic neuron membranes and regulate neuron survival, partly through RAC1 activation. As a regulator of lipid metabolism in the adipose tissue, mediates the crosstalk between adipocytes, gut microbiota and immune cells to control body temperature and weight. In particular, regulates energy homeostasis by promoting cold-induced brown or beige adipocyte differentiation program to generate heat from fatty acids and glucose. Has limited D-type phospholipase activity toward N-acyl lyso-NAPEs.
• Tissue Specificity: Widely expressed. Highest expression in brain, kidney and testis (at protein level). Expressed in adipose tissue (at protein level).
• KEGG Pathway: Retrograde endocan.binoid sig.ling (hsa04723)
• Reactome Pathway: Biosynthesis of A2E, implicated in retinal degradation (R-HSA-2466712)
• BioCyc Pathway: MetaCyc:ENSG00000161048-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 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 N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPEPLD).	[10]

References

• [1] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [2] 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.
• [3] 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.
• [4] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [5] 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.
• [6] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [7] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.