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peptidyl arginine deiminase 4

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2877

Nomenclature: peptidyl arginine deiminase 4

Family: 3.5.3.15 Peptidyl arginine deiminases (PADI)

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 663 1p36.13 PADI4 peptidyl arginine deiminase 4
Mouse - 666 4 72.34 cM Padi4 peptidyl arginine deiminase, type IV
Rat - 666 5q36 Padi4 peptidyl arginine deiminase 4
Previous and Unofficial Names Click here for help
peptidyl arginine deiminase, type IV | peptidyl arginine deiminase
Database Links Click here for help
Alphafold Q9UM07 (Hs), Q9Z183 (Mm), O88807 (Rn)
BRENDA 3.5.3.15
CATH/Gene3D 2.60.40.1700
ChEMBL Target CHEMBL6111 (Hs), CHEMBL3407322 (Mm)
Ensembl Gene ENSG00000159339 (Hs), ENSMUSG00000025330 (Mm), ENSRNOG00000006855 (Rn)
Entrez Gene 23569 (Hs), 18602 (Mm), 29512 (Rn)
Human Protein Atlas ENSG00000159339 (Hs)
KEGG Enzyme 3.5.3.15
KEGG Gene hsa:23569 (Hs), mmu:18602 (Mm), rno:29512 (Rn)
OMIM 605347 (Hs)
Pharos Q9UM07 (Hs)
RefSeq Nucleotide NM_011061 (Mm), NM_017227 (Rn)
RefSeq Protein NP_036519 (Hs), NM_012387 (Hs), NP_035191 (Mm), NP_058923 (Rn)
SynPHARM 83479 (in complex with o-F-amidine)
UniProtKB Q9UM07 (Hs), Q9Z183 (Mm), O88807 (Rn)
Wikipedia PADI4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human peptidylarginine deiminase 4 in complex with o-F-amidine.
PDB Id:  3B1U
Ligand:  o-F-amidine
Resolution:  2.1Å
Species:  Human
References:  2
Enzyme Reaction Click here for help
EC Number: 3.5.3.15 protein L-arginine + H2O <=> protein L-citrulline + NH3

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
JBI-589 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 6.0 – 7.0 pIC50 5,9
⤷ pIC50 6.9 (IC50 1.22x10-7 M) [5]
Description: Inhibition of PADI4 enzymatic activity in vitro, in a biochemical assay measuring ammonia release
pIC50 6.0 – 7.0 (IC50 1x10-6 – 1x10-7 M) [9]
Description: Measuring inhibition of histone citrullination in neutrophils
o-F-amidine Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Irreversible inhibition 5.7 pIC50 2
⤷ pIC50 5.7 (IC50 1.9x10-6 M) [2]
streptonigrin Small molecule or natural product Primary target of this compound N/A Inhibition 5.6 pIC50 10
⤷ pIC50 5.6 (IC50 2.5x10-6 M) [10]
compound 3 [PMID: 24440480] Small molecule or natural product N/A Irreversible inhibition - - 3
⤷ [3]
Description: Kinact/KI = 5.7x103 M-1 min-1
compound 14b [PMID: 25742366] Small molecule or natural product Click here for species-specific activity table Hs Irreversible inhibition - - 8
⤷ [8]
Description: Kinact/KI = 1.46x103 M-1 min-1
Cl-amidine Small molecule or natural product Click here for species-specific activity table Hs Inhibition - - 8
⤷ [8]
Description: Kinact/KI = 1.77x103 M-1 min-1
View species-specific inhibitor tables
Immunopharmacology Comments
PADI4 is essential for neutrophil extracellular trap (NET) formation (NETosis) in pathogen elimination. PADI4-formed NETs containing hypercitrullinated histone H3 are detected in several systemic autoimmune diseases, including lupus and rheumatoid arthritis [4]. PADI4 polymorphisms are associated with susceptibility to rheumatoid arthritis in several populations [1,6-7,11-12,14]. PADI4 knockout mice exhibit decreased severity of experimental autoimmune arthritis,[13].
Immuno Process Associations
Immuno Process:  Inflammation
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Rheumatoid arthritis
Disease Ontology: DOID:7148
OMIM: 180300

References

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1. Baños-Hernández CJ, Navarro-Zarza JE, Parra-Rojas I, Vázquez-Villamar M, Ramón Padilla-Gutiérrez J, Valle Y, Reyes-Castillo Z, Magdalena Torres-Carrillo N, García-Arellano S, Brennan-Bourdon LM et al.. (2017) PADI4 polymorphisms and the functional haplotype are associated with increased rheumatoid arthritis susceptibility: A replication study in a Southern Mexican population. Hum Immunol, 78 (9): 553-558. [PMID:28551357]

2. Causey CP, Jones JE, Slack JL, Kamei D, Jones LE, Subramanian V, Knuckley B, Ebrahimi P, Chumanevich AA, Luo Y et al.. (2011) The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors. J Med Chem, 54 (19): 6919-35. [PMID:21882827]

3. Dreyton CJ, Anderson ED, Subramanian V, Boger DL, Thompson PR. (2014) Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation. Bioorg Med Chem, 22 (4): 1362-9. [PMID:24440480]

4. Fuhrmann J, Thompson PR. (2016) Protein Arginine Methylation and Citrullination in Epigenetic Regulation. ACS Chem Biol, 11 (3): 654-68. [PMID:26686581]

5. Gajendran C, Fukui S, Sadhu NM, Zainuddin M, Rajagopal S, Gosu R, Gutch S, Fukui S, Sheehy CE, Chu L et al.. (2023) Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4. Sci Rep, 13 (1): 3189. [PMID:36823444]

6. Gong LL, Chang J, Yang YM. (2016) Association between peptidyl arginine deiminase 4 (PADI4)-104C/T polymorphism and rheumatoid arthritis: a meta-analysis in the Chinese population. Genet Mol Res, 15 (3). [PMID:27706751]

7. Hisa K, Yanagimachi MD, Naruto T, Miyamae T, Kikuchi M, Hara R, Imagawa T, Yokota S, Mori M. (2017) PADI4 and the HLA-DRB1 shared epitope in juvenile idiopathic arthritis. PLoS ONE, 12 (2): e0171961. [PMID:28182665]

8. Jamali H, Khan HA, Stringer JR, Chowdhury S, Ellman JA. (2015) Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method. J Am Chem Soc, 137 (10): 3616-21. [PMID:25742366]

9. Kazmi SMI, Rajagopal S, Sivanandan D. (2022) Method and compound for use, in treating and/or preventing netosis. Patent number: WO2022034616A1. Assignee: Jubilant Epipad LLC, Sridharan Rajagopal. Priority date: 12/08/2020. Publication date: 17/02/2022.

10. Knuckley B, Jones JE, Bachovchin DA, Slack J, Causey CP, Brown SJ, Rosen H, Cravatt BF, Thompson PR. (2010) A fluopol-ABPP HTS assay to identify PAD inhibitors. Chem Commun (Camb.), 46 (38): 7175-7. [PMID:20740228]

11. Shamsian E, Azarian M, Akhlaghi M, Samaei M, Jamshidi AR, Assar S, Shakiba Y, Gharibdoost F, Nourijelyani K, Mahmoudi M. (2016) PADI4 Polymorphisms in Iranian Patients with Rheumatoid Arthritis. Acta Reumatol Port, 41 (4): 338-343. [PMID:27182695]

12. Song ST, Kim SS, Kim JY, Lee SY, Kim K, Kwon IS, Kim JN, Park WH, Yoo IS, Yoo SJ et al.. (2016) Association of Single Nucleotide Polymorphisms of PADI4 and HLA-DRB1 Alleles with Susceptibility to Rheumatoid Arthritis-Related Lung Diseases. Lung, 194 (5): 745-53. [PMID:27372294]

13. Suzuki A, Kochi Y, Shoda H, Seri Y, Fujio K, Sawada T, Yamada R, Yamamoto K. (2016) Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice. BMC Musculoskelet Disord, 17: 205. [PMID:27150598]

14. Too CL, Murad S, Dhaliwal JS, Larsson P, Jiang X, Ding B, Alfredsson L, Klareskog L, Padyukov L. (2012) Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: evidence from MyEIRA study and meta-analysis. Arthritis Res Ther, 14 (6): R250. [PMID:23164236]

How to cite this page

3.5.3.15 Peptidyl arginine deiminases (PADI): peptidyl arginine deiminase 4. Last modified on 13/03/2023. Accessed on 09/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2877.