Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL07SP2)

• DOT Name: 5'-3' exonuclease PLD3 (PLD3)
• Synonyms: EC 3.1.16.1; Choline phosphatase 3; HindIII K4L homolog; Hu-K4; Phosphatidylcholine-hydrolyzing phospholipase D3; Phospholipase D3; PLD 3
• Gene Name: PLD3
• Related Disease:
  Amyloidosis
  Atopic dermatitis
  Conjunctivitis
  Keratoconjunctivitis
  Rheumatoid arthritis
  Systemic sclerosis
  Vascular purpura
  Spinocerebellar ataxia 46
• UniProt ID: PLD3_HUMAN
• PDB ID: 8Q1K; 8Q1X
• EC Number: 3.1.16.1
• Pfam ID: PF13918
• Sequence:
  MKPKLMYQELKVPAEEPANELPMNEIEAWKAAEKKARWVLLVLILAVVGFGALMTQLFLW
  EYGDLHLFGPNQRPAPCYDPCEAVLVESIPEGLDFPNASTGNPSTSQAWLGLLAGAHSSL
  DIASFYWTLTNNDTHTQEPSAQQGEEVLRQLQTLAPKGVNVRIAVSKPSGPQPQADLQAL
  LQSGAQVRMVDMQKLTHGVLHTKFWVVDQTHFYLGSANMDWRSLTQVKELGVVMYNCSCL
  ARDLTKIFEAYWFLGQAGSSIPSTWPRFYDTRYNQETPMEICLNGTPALAYLASAPPPLC
  PSGRTPDLKALLNVVDNARSFIYVAVMNYLPTLEFSHPHRFWPAIDDGLRRATYERGVKV
  RLLISCWGHSEPSMRAFLLSLAALRDNHTHSDIQVKLFVVPADEAQARIPYARVNHNKYM
  VTERATYIGTSNWSGNYFTETAGTSLLVTQNGRGGLRSQLEAIFLRDWDSPYSHDLDTSA
  DSVGNACRLL
• Function: 5'->3' DNA exonuclease which digests single-stranded DNA (ssDNA). Regulates inflammatory cytokine responses via the degradation of nucleic acids, by reducing the concentration of ssDNA able to stimulate TLR9, a nucleotide-sensing receptor in collaboration with PLD4. May be important in myotube formation. Plays a role in lysosomal homeostasis. Involved in the regulation of endosomal protein sorting.
• Tissue Specificity: Widely expressed. In the brain, high levels of expression are detected in the frontal, temporal and occipital cortices and hippocampus. Expressed at low level in corpus callosum.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  Synthesis of PG (R-HSA-1483148)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyloidosis	DISHTAI2	Strong	Altered Expression	[1]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[2]
Conjunctivitis	DISGOZ4P	Strong	Genetic Variation	[3]
Keratoconjunctivitis	DISOYCQC	Strong	Biomarker	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[5]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[5]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[6]
Spinocerebellar ataxia 46	DISPAP4I	Supportive	Autosomal dominant	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	5'-3' exonuclease PLD3 (PLD3) affects the response to substance of Methotrexate.	[26]

19 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 5'-3' exonuclease PLD3 (PLD3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 5'-3' exonuclease PLD3 (PLD3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 5'-3' exonuclease PLD3 (PLD3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 5'-3' exonuclease PLD3 (PLD3).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 5'-3' exonuclease PLD3 (PLD3).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of 5'-3' exonuclease PLD3 (PLD3).	[16]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of 5'-3' exonuclease PLD3 (PLD3).	[17]
Dopamine	DMPGUCF	Approved	Dopamine affects the expression of 5'-3' exonuclease PLD3 (PLD3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 5'-3' exonuclease PLD3 (PLD3).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 5'-3' exonuclease PLD3 (PLD3).	[21]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of 5'-3' exonuclease PLD3 (PLD3).	[24]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of 5'-3' exonuclease PLD3 (PLD3).	[25]

References

• [1] V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function.Neurobiol Dis. 2019 Sep;129:182-194. doi: 10.1016/j.nbd.2019.05.015. Epub 2019 May 20.
• [2] Increasing severity of atopic dermatitis is associated with a negative impact on work productivity among adults with atopic dermatitis in France, Germany, the U.K. and the U.S.A.Br J Dermatol. 2020 Apr;182(4):1007-1016. doi: 10.1111/bjd.18296. Epub 2019 Sep 8.
• [3] Genome types of adenovirus types 19 and 37 isolated from patients with conjunctivitis in Hiroshima City.J Med Virol. 1988 Sep;26(1):15-22. doi: 10.1002/jmv.1890260104.
• [4] Hemorrhagic viral keratoconjunctivitis in Taiwan caused by adenovirus types 19 and 37: applicability of polymerase chain reaction-restriction fragment length polymorphism in detecting adenovirus genotypes.Cornea. 2001 Apr;20(3):295-300. doi: 10.1097/00003226-200104000-00011.
• [5] PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing.Nat Immunol. 2018 Sep;19(9):942-953. doi: 10.1038/s41590-018-0179-y. Epub 2018 Aug 13.
• [6] Hereditary ataxias and paraparesias: clinical and genetic update. Curr Opin Neurol. 2018 Aug;31(4):462-471. doi: 10.1097/WCO.0000000000000585.
• [7] 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.
• [8] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] 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.
• [14] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [18] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.
• [22] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [23] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [24] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [25] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.