Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5I74II)

• DOT Name: 5'-3' exonuclease PLD4 (PLD4)
• Synonyms: EC 3.1.16.1; Choline phosphatase 4; Phosphatidylcholine-hydrolyzing phospholipase D4; Phospholipase D family member 4; Phospholipase D4; PLD 4
• Gene Name: PLD4
• Related Disease:
  Alzheimer disease
  Autoimmune disease
  Colon cancer
  Colon carcinoma
  Hepatitis
  Inflammation
  Renal fibrosis
  Rheumatoid arthritis
  Systemic lupus erythematosus
  Usher syndrome
  Systemic sclerosis
• UniProt ID: PLD4_HUMAN
• EC Number: 3.1.16.1
• Pfam ID: PF13918
• Sequence:
  MLKPLWKAAVAPTWPCSMPPRRPWDREAGTLQVLGALAVLWLGSVALICLLWQVPRPPTW
  GQVQPKDVPRSWEHGSSPAWEPLEAEARQQRDSCQLVLVESIPQDLPSAAGSPSAQPLGQ
  AWLQLLDTAQESVHVASYYWSLTGPDIGVNDSSSQLGEALLQKLQQLLGRNISLAVATSS
  PTLARTSTDLQVLAARGAHVRQVPMGRLTRGVLHSKFWVVDGRHIYMGSANMDWRSLTQV
  KELGAVIYNCSHLAQDLEKTFQTYWVLGVPKAVLPKTWPQNFSSHFNRFQPFHGLFDGVP
  TTAYFSASPPALCPQGRTRDLEALLAVMGSAQEFIYASVMEYFPTTRFSHPPRYWPVLDN
  ALRAAAFGKGVRVRLLVGCGLNTDPTMFPYLRSLQALSNPAANVSVDVKVFIVPVGNHSN
  IPFSRVNHSKFMVTEKAAYIGTSNWSEDYFSSTAGVGLVVTQSPGAQPAGATVQEQLRQL
  FERDWSSRYAVGLDGQAPGQDCVWQG
• 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. Involved in phagocytosis of activated microglia.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  Synthesis of PG (R-HSA-1483148)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Hepatitis	DISXXX35	Strong	Genetic Variation	[1]
Inflammation	DISJUQ5T	Strong	Biomarker	[1]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[5]
Usher syndrome	DIS9YIS7	moderate	Biomarker	[6]
Systemic sclerosis	DISF44L6	Limited	Biomarker	[1]

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 5'-3' exonuclease PLD4 (PLD4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 5'-3' exonuclease PLD4 (PLD4).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 5'-3' exonuclease PLD4 (PLD4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 5'-3' exonuclease PLD4 (PLD4).	[9]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol affects the expression of 5'-3' exonuclease PLD4 (PLD4).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 5'-3' exonuclease PLD4 (PLD4).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 5'-3' exonuclease PLD4 (PLD4).	[13]

References

• [1] 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.
• [2] PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population.Arthritis Rheum. 2013 Feb;65(2):472-80. doi: 10.1002/art.37777.
• [3] PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells.Oncol Rep. 2017 Jan;37(1):408-416. doi: 10.3892/or.2016.5216. Epub 2016 Nov 3.
• [4] Targeting Phospholipase D4 Attenuates Kidney Fibrosis.J Am Soc Nephrol. 2017 Dec;28(12):3579-3589. doi: 10.1681/ASN.2016111222. Epub 2017 Aug 16.
• [5] PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes.Ann Rheum Dis. 2019 Apr;78(4):509-518. doi: 10.1136/annrheumdis-2018-214116. Epub 2019 Jan 24.
• [6] Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.
• [7] 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.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J Exp Med. 2010 Apr 12;207(4):731-50. doi: 10.1084/jem.20091488. Epub 2010 Apr 5.
• [11] 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.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.