Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMVUKW6)

• DOT Name: Phospholipase D1 (PLD1)
• Synonyms: PLD 1; hPLD1; EC 3.1.4.4; Choline phosphatase 1; Phosphatidylcholine-hydrolyzing phospholipase D1
• Gene Name: PLD1
• Related Disease: Cardiac valvular defect, developmental
• UniProt ID: PLD1_HUMAN
• PDB ID: 6U8Z
• EC Number: 3.1.4.4
• Pfam ID: PF00169 ; PF00614 ; PF13091 ; PF00787
• Sequence:
  MSLKNEPRVNTSALQKIAADMSNIIENLDTRELHFEGEEVDYDVSPSDPKIQEVYIPFSA
  IYNTQGFKEPNIQTYLSGCPIKAQVLEVERFTSTTRVPSINLYTIELTHGEFKWQVKRKF
  KHFQEFHRELLKYKAFIRIPIPTRRHTFRRQNVREEPREMPSLPRSSENMIREEQFLGRR
  KQLEDYLTKILKMPMYRNYHATTEFLDISQLSFIHDLGPKGIEGMIMKRSGGHRIPGLNC
  CGQGRACYRWSKRWLIVKDSFLLYMKPDSGAIAFVLLVDKEFKIKVGKKETETKYGIRID
  NLSRTLILKCNSYRHARWWGGAIEEFIQKHGTNFLKDHRFGSYAAIQENALAKWYVNAKG
  YFEDVANAMEEANEEIFITDWWLSPEIFLKRPVVEGNRWRLDCILKRKAQQGVRIFIMLY
  KEVELALGINSEYTKRTLMRLHPNIKVMRHPDHVSSTVYLWAHHEKLVIIDQSVAFVGGI
  DLAYGRWDDNEHRLTDVGSVKRVTSGPSLGSLPPAAMESMESLRLKDKNEPVQNLPIQKS
  IDDVDSKLKGIGKPRKFSKFSLYKQLHRHHLHDADSISSIDSTSSYFNHYRSHHNLIHGL
  KPHFKLFHPSSESEQGLTRPHADTGSIRSLQTGVGELHGETRFWHGKDYCNFVFKDWVQL
  DKPFADFIDRYSTPRMPWHDIASAVHGKAARDVARHFIQRWNFTKIMKSKYRSLSYPFLL
  PKSQTTAHELRYQVPGSVHANVQLLRSAADWSAGIKYHEESIHAAYVHVIENSRHYIYIE
  NQFFISCADDKVVFNKIGDAIAQRILKAHRENQKYRVYVVIPLLPGFEGDISTGGGNALQ
  AIMHFNYRTMCRGENSILGQLKAELGNQWINYISFCGLRTHAELEGNLVTELIYVHSKLL
  IADDNTVIIGSANINDRSMLGKRDSEMAVIVQDTETVPSVMDGKEYQAGRFARGLRLQCF
  RVVLGYLDDPSEDIQDPVSDKFFKEVWVSTAARNATIYDKVFRCLPNDEVHNLIQLRDFI
  NKPVLAKEDPIRAEEELKKIRGFLVQFPFYFLSEESLLPSVGTKEAIVPMEVWT
• Function: Function as phospholipase selective for phosphatidylcholine. Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic.
• Tissue Specificity: Expressed abundantly in the pancreas and heart and at high levels in brain, placenta, spleen, uterus and small intestine.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
  Ras sig.ling pathway (hsa04014)
  cAMP sig.ling pathway (hsa04024)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Glutamatergic sy.pse (hsa04724)
  GnRH sig.ling pathway (hsa04912)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Pancreatic cancer (hsa05212)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Synthesis of PA (R-HSA-1483166)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  Neutrophil degranulation (R-HSA-6798695)
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOG GTPase cycle (R-HSA-9013408)
  Synthesis of PG (R-HSA-1483148)
• BioCyc Pathway: MetaCyc:HS01185-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac valvular defect, developmental	DIS9I1G2	Strong	Autosomal recessive	[1]

27 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 D1 (PLD1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipase D1 (PLD1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phospholipase D1 (PLD1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipase D1 (PLD1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipase D1 (PLD1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phospholipase D1 (PLD1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phospholipase D1 (PLD1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phospholipase D1 (PLD1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Phospholipase D1 (PLD1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Phospholipase D1 (PLD1).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phospholipase D1 (PLD1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phospholipase D1 (PLD1).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Phospholipase D1 (PLD1).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Phospholipase D1 (PLD1).	[16]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Phospholipase D1 (PLD1).	[17]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Phospholipase D1 (PLD1).	[18]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Phospholipase D1 (PLD1).	[19]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Phospholipase D1 (PLD1).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipase D1 (PLD1).	[21]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Phospholipase D1 (PLD1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phospholipase D1 (PLD1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Phospholipase D1 (PLD1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phospholipase D1 (PLD1).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phospholipase D1 (PLD1).	[27]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Phospholipase D1 (PLD1).	[28]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Phospholipase D1 (PLD1).	[29]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Phospholipase D1 (PLD1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Phospholipase D1 (PLD1).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Phospholipase D1 (PLD1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Phospholipase D1 (PLD1).	[25]

References

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• [4] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [5] 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.
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• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] 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.
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• [11] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [12] Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling. Neurotoxicology. 2015 Sep;50:56-70.
• [13] 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.
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• [16] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [17] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [18] 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.
• [19] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [20] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [23] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [29] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [30] 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.