Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDGF4J5)

• DOT Name: Protein-arginine deiminase type-4 (PADI4)
• Synonyms: EC 3.5.3.15; HL-60 PAD; Peptidylarginine deiminase IV; Protein-arginine deiminase type IV
• Gene Name: PADI4
• UniProt ID: PADI4_HUMAN
• PDB ID: 1WD8; 1WD9; 1WDA; 2DEW; 2DEX; 2DEY; 2DW5; 3APM; 3APN; 3B1T; 3B1U; 4DKT; 4X8C; 4X8G; 5N0M; 5N0Y; 5N0Z; 5N1B; 8GOD
• EC Number: 3.5.3.15
• Pfam ID: PF03068 ; PF08527 ; PF08526
• Sequence:
  MAQGTLIRVTPEQPTHAVCVLGTLTQLDICSSAPEDCTSFSINASPGVVVDIAHGPPAKK
  KSTGSSTWPLDPGVEVTLTMKVASGSTGDQKVQISYYGPKTPPVKALLYLTGVEISLCAD
  ITRTGKVKPTRAVKDQRTWTWGPCGQGAILLVNCDRDNLESSAMDCEDDEVLDSEDLQDM
  SLMTLSTKTPKDFFTNHTLVLHVARSEMDKVRVFQATRGKLSSKCSVVLGPKWPSHYLMV
  PGGKHNMDFYVEALAFPDTDFPGLITLTISLLDTSNLELPEAVVFQDSVVFRVAPWIMTP
  NTQPPQEVYACSIFENEDFLKSVTTLAMKAKCKLTICPEEENMDDQWMQDEMEIGYIQAP
  HKTLPVVFDSPRNRGLKEFPIKRVMGPDFGYVTRGPQTGGISGLDSFGNLEVSPPVTVRG
  KEYPLGRILFGDSCYPSNDSRQMHQALQDFLSAQQVQAPVKLYSDWLSVGHVDEFLSFVP
  APDRKGFRLLLASPRSCYKLFQEQQNEGHGEALLFEGIKKKKQQKIKNILSNKTLREHNS
  FVERCIDWNRELLKRELGLAESDIIDIPQLFKLKEFSKAEAFFPNMVNMLVLGKHLGIPK
  PFGPVINGRCCLEEKVCSLLEPLGLQCTFINDFFTYHIRHGEVHCGTNVRRKPFSFKWWN
  MVP
• Function: Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance. Citrullinates histone H1 at 'Arg-54' (to form H1R54ci), histone H3 at 'Arg-2', 'Arg-8', 'Arg-17' and/or 'Arg-26' (to form H3R2ci, H3R8ci, H3R17ci, H3R26ci, respectively) and histone H4 at 'Arg-3' (to form H4R3ci). Acts as a key regulator of stem cell maintenance by mediating citrullination of histone H1: citrullination of 'Arg-54' of histone H1 (H1R54ci) results in H1 displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci. Required for the formation of neutrophil extracellular traps (NETs); NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation. Citrullination of histone H3 prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.
• Tissue Specificity: Expressed in eosinophils and neutrophils, not expressed in peripheral monocytes or lymphocytes.
• KEGG Pathway: Neutrophil extracellular trap formation (hsa04613)
• Reactome Pathway: Chromatin modifying enzymes (R-HSA-3247509)
• BioCyc Pathway: MetaCyc:HS08389-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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 Protein-arginine deiminase type-4 (PADI4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein-arginine deiminase type-4 (PADI4).	[7]

7 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 Protein-arginine deiminase type-4 (PADI4).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein-arginine deiminase type-4 (PADI4).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein-arginine deiminase type-4 (PADI4).	[4]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Protein-arginine deiminase type-4 (PADI4).	[5]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein-arginine deiminase type-4 (PADI4).	[8]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein-arginine deiminase type-4 (PADI4).	[9]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Protein-arginine deiminase type-4 (PADI4).	[10]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Protein-arginine deiminase type-4 (PADI4).	[6]

References

• [1] 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.
• [2] 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.
• [3] Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility. Cell Rep. 2018 Feb 6;22(6):1473-1483. doi: 10.1016/j.celrep.2018.01.031.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] Arginine methylation provides epigenetic transcription memory for retinoid-induced differentiation in myeloid cells. Mol Cell Biol. 2005 Jul;25(13):5648-63.
• [6] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [7] 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.
• [8] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [9] 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.
• [10] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.