Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQHAXM)

• DTT Name: Peptidyl arginine deiminase type IV (PADI4)
• Synonyms: Protein-arginine deiminase type-4; Protein-arginine deiminase type IV; Peptidylarginine deiminase IV; PDI5; PADI5; PAD4; HL-60 PAD
• Gene Name: PADI4
• DTT Type: Literature-reported target; [1]
• BioChemical Class: Carbon-nitrogen hydrolase
• UniProt ID: PADI4_HUMAN
• TTD ID: T50429
• EC Number: EC 3.5.3.15
• Sequence:
  MAQGTLIRVTPEQPTHAVCVLGTLTQLDICSSAPEDCTSFSINASPGVVVDIAHGPPAKK
  KSTGSSTWPLDPGVEVTLTMKVASGSTGDQKVQISYYGPKTPPVKALLYLTGVEISLCAD
  ITRTGKVKPTRAVKDQRTWTWGPCGQGAILLVNCDRDNLESSAMDCEDDEVLDSEDLQDM
  SLMTLSTKTPKDFFTNHTLVLHVARSEMDKVRVFQATRGKLSSKCSVVLGPKWPSHYLMV
  PGGKHNMDFYVEALAFPDTDFPGLITLTISLLDTSNLELPEAVVFQDSVVFRVAPWIMTP
  NTQPPQEVYACSIFENEDFLKSVTTLAMKAKCKLTICPEEENMDDQWMQDEMEIGYIQAP
  HKTLPVVFDSPRNRGLKEFPIKRVMGPDFGYVTRGPQTGGISGLDSFGNLEVSPPVTVRG
  KEYPLGRILFGDSCYPSNDSRQMHQALQDFLSAQQVQAPVKLYSDWLSVGHVDEFLSFVP
  APDRKGFRLLLASPRSCYKLFQEQQNEGHGEALLFEGIKKKKQQKIKNILSNKTLREHNS
  FVERCIDWNRELLKRELGLAESDIIDIPQLFKLKEFSKAEAFFPNMVNMLVLGKHLGIPK
  PFGPVINGRCCLEEKVCSLLEPLGLQCTFINDFFTYHIRHGEVHCGTNVRRKPFSFKWWN
  MVP
• Function: 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. 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. 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.
• KEGG Pathway: Neutrophil extracellular trap formation (hsa04613)
• Reactome Pathway: Chromatin modifying enzymes (R-HSA-3247509)
• BioCyc Pathway: MetaCyc:HS08389-MON

Molecular Interaction Atlas (MIA) of This DTT

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cl-amidine	DMRV89X	Discovery agent	N.A.	Investigative	[2]
PMID24440480C3	DMHQK54	Discovery agent	N.A.	Investigative	[3]
PMID25742366C14b	DMDYT6P	Discovery agent	N.A.	Investigative	[2]
streptonigrin	DM0HOEA	Discovery agent	N.A.	Investigative	[1]

References

• [1] A fluopol-ABPP HTS assay to identify PAD inhibitors. Chem Commun (Camb). 2010 Oct 14;46(38):7175-7.
• [2] Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method. J Am Chem Soc. 2015 Mar 18;137(10):3616-21.
• [3] Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation. Bioorg Med Chem. 2014 Feb 15;22(4):1362-9.