Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOHM9QM)

• DOT Name: Lysophospholipase D GDPD3 (GDPD3)
• Synonyms: EC 3.1.4.-; Glycerophosphodiester phosphodiesterase 7; Glycerophosphodiester phosphodiesterase domain-containing protein 3
• Gene Name: GDPD3
• Related Disease:
  Neoplasm
  Advanced cancer
  Herpes simplex infection
  Lysosomal lipid storage disorder
• UniProt ID: GDPD3_HUMAN
• EC Number: 3.1.4.-
• Pfam ID: PF03009
• Sequence:
  MSLLLYYALPALGSYAMLSIFFLRRPHLLHTPRAPTFRIRLGAHRGGSGELLENTMEAME
  NSMAQRSDLLELDCQLTRDRVVVVSHDENLCRQSGLNRDVGSLDFEDLPLYKEKLEVYFS
  PGHFAHGSDRRMVRLEDLFQRFPRTPMSVEIKGKNEELIREIAGLVRRYDRNEITIWASE
  KSSVMKKCKAANPEMPLSFTISRGFWVLLSYYLGLLPFIPIPEKFFFCFLPNIINRTYFP
  FSCSCLNQLLAVVSKWLIMRKSLIRHLEERGVQVVFWCLNEESDFEAAFSVGATGVITDY
  PTALRHYLDNHGPAARTS
• Function: Hydrolyzes lysoglycerophospholipids to produce lysophosphatidic acid (LPA) and the corresponding amines. Shows a preference for 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF), lysophosphatidylcholine (lyso-PC) and N-acylethanolamine lysophospholipids. Does not display glycerophosphodiester phosphodiesterase activity, since it cannot hydrolyze either glycerophosphoinositol or glycerophosphocholine.
• Tissue Specificity: Widely expressed, with high level in kidney and ovary.
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycerophospholipid catabolism (R-HSA-6814848)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Disputed	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Herpes simplex infection	DISL1SAV	Limited	Biomarker	[2]
Lysosomal lipid storage disorder	DISXQRTX	Limited	Biomarker	[3]

2 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 Lysophospholipase D GDPD3 (GDPD3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Lysophospholipase D GDPD3 (GDPD3).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[8]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Lysophospholipase D GDPD3 (GDPD3).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[10]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[3]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[3]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[13]
Thioridazine	DM35M8J	Approved	Thioridazine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[3]
Imipramine	DM2NUH3	Approved	Imipramine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
Clomipramine	DMINRKW	Approved	Clomipramine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[3]
Citalopram	DM2G9AE	Approved	Citalopram increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[14]
Loratadine	DMF3AN7	Approved	Loratadine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
Flecainide	DMSQDLE	Approved	Flecainide increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
Perhexiline	DMINO7Z	Approved	Perhexiline increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
Doxepin	DMPI98T	Approved	Doxepin increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[15]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[3]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[16]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[16]
Chlorcyclizine	DM3L52Q	Phase 1	Chlorcyclizine increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[11]
ZIMELIDINE	DMNI3U2	Withdrawn from market	ZIMELIDINE increases the expression of Lysophospholipase D GDPD3 (GDPD3).	[3]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Lysophospholipase D GDPD3 (GDPD3).	[19]

References

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• [2] Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors.Mol Cancer Ther. 2017 Sep;16(9):1922-1933. doi: 10.1158/1535-7163.MCT-17-0071. Epub 2017 May 18.
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• [4] 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.
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• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [10] 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.
• [11] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [12] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [13] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [14] In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol Sci. 2007 Sep;99(1):162-73.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.