Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT5T45Q)

• DOT Name: Patatin-like phospholipase domain-containing protein 6 (PNPLA6)
• Synonyms: EC 3.1.1.5; Neuropathy target esterase
• Gene Name: PNPLA6
• Related Disease:
  Ataxia-hypogonadism-choroidal dystrophy syndrome
  PNPLA6-related spastic paraplegia with or without ataxia
  Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome
  Hereditary spastic paraplegia 39
  Cerebellar ataxia-hypogonadism syndrome
  Laurence-Moon syndrome
  Trichomegaly-retina pigmentary degeneration-dwarfism syndrome
• UniProt ID: PLPL6_HUMAN
• EC Number: 3.1.1.5
• Pfam ID: PF00027 ; PF01734
• Sequence:
  MEAPLQTGMMGTSSHGLATNSSGAKVAERDGFQDVLAPGEGSAGRICGAQPVPFVPQVLG
  VMIGAGVAVVVTAVLILLVVRRLRVPKTPAPDGPRYRFRKRDKVLFYGRKIMRKVSQSTS
  SLVDTSVSATSRPRMRKKLKMLNIAKKILRIQKETPTLQRKEPPPAVLEADLTEGDLANS
  HLPSEVLYMLKNVRVLGHFEKPLFLELCRHMVFQRLGQGDYVFRPGQPDASIYVVQDGLL
  ELCLPGPDGKECVVKEVVPGDSVNSLLSILDVITGHQHPQRTVSARAARDSTVLRLPVEA
  FSAVFTKYPESLVRVVQIIMVRLQRVTFLALHNYLGLTNELFSHEIQPLRLFPSPGLPTR
  TSPVRGSKRMVSTSATDEPRETPGRPPDPTGAPLPGPTGDPVKPTSLETPSAPLLSRCVS
  MPGDISGLQGGPRSDFDMAYERGRISVSLQEEASGGSLAAPARTPTQEPREQPAGACEYS
  YCEDESATGGCPFGPYQGRQTSSIFEAAKQELAKLMRIEDPSLLNSRVLLHHAKAGTIIA
  RQGDQDVSLHFVLWGCLHVYQRMIDKAEDVCLFVAQPGELVGQLAVLTGEPLIFTLRAQR
  DCTFLRISKSDFYEIMRAQPSVVLSAAHTVAARMSPFVRQMDFAIDWTAVEAGRALYRQG
  DRSDCTYIVLNGRLRSVIQRGSGKKELVGEYGRGDLIGVVEALTRQPRATTVHAVRDTEL
  AKLPEGTLGHIKRRYPQVVTRLIHLLSQKILGNLQQLQGPFPAGSGLGVPPHSELTNPAS
  NLATVAILPVCAEVPMVAFTLELQHALQAIGPTLLLNSDIIRARLGASALDSIQEFRLSG
  WLAQQEDAHRIVLYQTDASLTPWTVRCLRQADCILIVGLGDQEPTLGQLEQMLENTAVRA
  LKQLVLLHREEGAGPTRTVEWLNMRSWCSGHLHLRCPRRLFSRRSPAKLHELYEKVFSRR
  ADRHSDFSRLARVLTGNTIALVLGGGGARGCSHIGVLKALEEAGVPVDLVGGTSIGSFIG
  ALYAEERSASRTKQRAREWAKSMTSVLEPVLDLTYPVTSMFTGSAFNRSIHRVFQDKQIE
  DLWLPYFNVTTDITASAMRVHKDGSLWRYVRASMTLSGYLPPLCDPKDGHLLMDGGYINN
  LPADIARSMGAKTVIAIDVGSQDETDLSTYGDSLSGWWLLWKRLNPWADKVKVPDMAEIQ
  SRLAYVSCVRQLEVVKSSSYCEYLRPPIDCFKTMDFGKFDQIYDVGYQYGKAVFGGWSRG
  NVIEKMLTDRRSTDLNESRRADVLAFPSSGFTDLAEIVSRIEPPTSYVSDGCADGEESDC
  LTEYEEDAGPDCSRDEGGSPEGASPSTASEMEEEKSILRQRRCLPQEPPGSATDA
• Function: Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho). This deacylation occurs at both sn-2 and sn-1 positions of PtdCho. Catalyzes the hydrolysis of several naturally occurring membrane-associated lipids. Hydrolyzes lysophospholipids and monoacylglycerols, preferring the 1-acyl to the 2-acyl isomer. Does not catalyze hydrolysis of di- or triacylglycerols or fatty acid amides.
• Tissue Specificity: Expressed in brain, placenta, kidney, neuron and skeletal muscle. Expressed in the developing eye, pituitary and brain.
• KEGG Pathway: Glycerophospholipid metabolism (hsa00564)
• Reactome Pathway: Glycerophospholipid catabolism (R-HSA-6814848)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia-hypogonadism-choroidal dystrophy syndrome	DISX5763	Definitive	Autosomal recessive	[1]
PNPLA6-related spastic paraplegia with or without ataxia	DISGKK7F	Definitive	Autosomal recessive	[2]
Retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome	DISZ1KU7	Definitive	Autosomal recessive	[2]
Hereditary spastic paraplegia 39	DIS9MUH1	Strong	Autosomal recessive	[3]
Cerebellar ataxia-hypogonadism syndrome	DISUEBFP	Supportive	Autosomal recessive	[4]
Laurence-Moon syndrome	DIS9L96U	Supportive	Autosomal recessive	[1]
Trichomegaly-retina pigmentary degeneration-dwarfism syndrome	DISLEZQ9	Supportive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Choline alfoscerate	DMOI1ZF	Approved	Patatin-like phospholipase domain-containing protein 6 (PNPLA6) affects the abundance of Choline alfoscerate.	[24]
Lysophosphatidylcholine	DMOGFVH	Investigative	Patatin-like phospholipase domain-containing protein 6 (PNPLA6) affects the abundance of Lysophosphatidylcholine.	[24]

6 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 Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[14]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[14]
Isoflurophate	DMBSK7X	Approved	Isoflurophate decreases the activity of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[17]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[19]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[21]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[22]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the activity of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[23]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon decreases the activity of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[15]
H-89	DM4RVGO	Investigative	H-89 decreases the expression of Patatin-like phospholipase domain-containing protein 6 (PNPLA6).	[22]

References

• [1] Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94. doi: 10.1136/jmedgenet-2014-102856. Epub 2014 Dec 5.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort. Neurogenetics. 2013 Nov;14(3-4):181-8. doi: 10.1007/s10048-013-0366-9. Epub 2013 Jun 4.
• [4] PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain. 2014 Jan;137(Pt 1):69-77. doi: 10.1093/brain/awt326. Epub 2013 Dec 19.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] 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.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] 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.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [14] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [15] Constructs of human neuropathy target esterase catalytic domain containing mutations related to motor neuron disease have altered enzymatic properties. Toxicol Lett. 2010 Jul 1;196(2):67-73. doi: 10.1016/j.toxlet.2010.03.1120. Epub 2010 Apr 9.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [20] 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.
• [21] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [22] Regulation of neuropathy target esterase by the cAMP/protein kinase A signal. Pharmacol Res. 2010 Sep;62(3):259-64. doi: 10.1016/j.phrs.2010.03.006. Epub 2010 Apr 7.
• [23] Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. Fundam Appl Toxicol. 1997 Jul;38(1):55-63.
• [24] The alteration of the expression level of neuropathy target esterase in human neuroblastoma SK-N-SH cells disrupts cellular phospholipids homeostasis. Toxicol In Vitro. 2023 Feb;86:105509. doi: 10.1016/j.tiv.2022.105509. Epub 2022 Nov 4.