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Literature summary extracted from

  • Jones, J.E.; Causey, C.P.; Knuckley, B.; Slack-Noyes, J.L.; Thompson, P.R.
    Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential (2009), Curr. Opin. Drug Discov. Devel., 12, 616-627.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
3.5.3.15 medicine PAD4 is a potential therapeutic target for the treatment of rheumatoid arthritis. PAD4 mutations are associated with anti-CCP antibody production and the increased expression of PAD4 in the rheumatoid arthritis synovium Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.5.3.15 2-chloroacetamidine
-
 Homo sapiens
3.5.3.15 chlortetracycline
-
 Homo sapiens
3.5.3.15 Cl-amidine highly potent PAD4 inactivator, inactivates the enzyme via the alkylation of Cys645 Homo sapiens
3.5.3.15 F-amidine highly potent PAD4 inactivator, inactivates the enzyme via the alkylation of Cys645 Homo sapiens
3.5.3.15 N-{(2S)-1-amino-5-[(2-chloroethanimidoyl)amino]-1-oxopentan-2-yl}benzamide
-
 Homo sapiens
3.5.3.15 N-{(2S)-1-amino-5-[(2-fluoroethanimidoyl)amino]-1-oxopentan-2-yl}benzamide
-
 Homo sapiens
3.5.3.15 N2-benzoyl-N5-(N,N-dimethylcarbamimidoyl)-L-ornithine inhibits PAD4 at high micromolar to millimolar concentrations Homo sapiens
3.5.3.15 paclitaxel inhibits PAD4 at high micromolar to millimolar concentrations Homo sapiens
3.5.3.15 tetracycline
-
 Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
3.5.3.15 cytoplasmic vesicle
-
 Homo sapiens 31410
-
3.5.3.15 nucleus
-
 Homo sapiens 5634
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
3.5.3.15 Ca2+ high concentrations of Ca2+ (more than 0.1 mM) are required for activity, the enzyme has 5 Ca2+ binding sites Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.5.3.15 protein L-Arg + H2O Homo sapiens
-
 protein citrulline + NH3
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
3.5.3.15 Homo sapiens
-
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
3.5.3.15 A-549 cell
-
 Homo sapiens
-
3.5.3.15 bladder carcinoma cell
-
 Homo sapiens
-
3.5.3.15 breast adenocarcinoma cell
-
 Homo sapiens
-
3.5.3.15 chondroma cell
-
 Homo sapiens
-
3.5.3.15 colorectal adenocarcinoma cell
-
 Homo sapiens
-
3.5.3.15 endometrial carcinoma cell
-
 Homo sapiens
-
3.5.3.15 eosinophil
-
 Homo sapiens
-
3.5.3.15 esophageal squamous cell carcinoma cell
-
 Homo sapiens
-
3.5.3.15 granulocyte
-
 Homo sapiens
-
3.5.3.15 hepatocellular carcinoma cell
-
 Homo sapiens
-
3.5.3.15 lung adenocarcinoma cell
-
 Homo sapiens
-
3.5.3.15 macrophage
-
 Homo sapiens
-
3.5.3.15 MCF-7 cell
-
 Homo sapiens
-
3.5.3.15 neutrophil
-
 Homo sapiens
-
3.5.3.15 ovarian cancer cell
-
 Homo sapiens
-
3.5.3.15 renal cancer cell
-
 Homo sapiens
-
3.5.3.15 SKOV-3 cell
-
 Homo sapiens
-
3.5.3.15 U-937 cell
-
 Homo sapiens
-
3.5.3.15 uterine adenocarcinoma cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.5.3.15 benzoyl-L-arginine amide + H2O best small-molecule substrate for PAD4 Homo sapiens ?
-
 ?
3.5.3.15 histone H2A-L-arginine + H2O
-
 Homo sapiens histone H2A-L-citrulline + NH3
-
 ?
3.5.3.15 histone H3-L-arginine + H2O
-
 Homo sapiens histone H3-L-citrulline + NH3
-
 ?
3.5.3.15 histone H4-L-arginine + H2O
-
 Homo sapiens histone H4-L-citrulline + NH3
-
 ?
3.5.3.15 p300-L-arginine + H2O
-
 Homo sapiens ?
-
 ?
3.5.3.15 protein L-Arg + H2O
-
 Homo sapiens protein citrulline + NH3
-
 ?
3.5.3.15 vimentin-L-arginine + H2O
-
 Homo sapiens vimentin-L-citrulline + NH3
-
 ?

Synonyms

EC Number Synonyms Comment Organism
3.5.3.15 PAD4 isozyme Homo sapiens
3.5.3.15 protein arginine deiminase 4 isozyme Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
3.5.3.15 7.6
-
-
 Homo sapiens

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
3.5.3.15 0.18
-
 Cl-amidine in 100 mM HEPES (pH 7.6), CaCl2 (10 mM), TCEP (0.5 mM), NaCl (50 mM), temperature not specified in the publication Homo sapiens
3.5.3.15 0.33
-
 F-amidine in 100 mM HEPES (pH 7.6), CaCl2 (10 mM), TCEP (0.5 mM), NaCl (50 mM), temperature not specified in the publication Homo sapiens
3.5.3.15 20
-
 2-chloroacetamidine IC50 above 0.5 mM, in 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), dithiothreitol (5 mM), at 37°C Homo sapiens

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
3.5.3.15 0.0074
-
 in 100 mM HEPES (pH 7.6), CaCl2 (10 mM), TCEP (0.5 mM), NaCl (50 mM), temperature not specified in the publication Homo sapiens N-{(2S)-1-amino-5-[(2-chloroethanimidoyl)amino]-1-oxopentan-2-yl}benzamide
3.5.3.15 0.022
-
 in 100 mM HEPES (pH 7.6), CaCl2 (10 mM), TCEP (0.5 mM), NaCl (50 mM), temperature not specified in the publication Homo sapiens F-amidine
3.5.3.15 0.022
-
 in 100 mM HEPES (pH 7.6), CaCl2 (10 mM), TCEP (0.5 mM), NaCl (50 mM), temperature not specified in the publication Homo sapiens Cl-amidine
3.5.3.15 0.024
-
 in 100 mM HEPES (pH 7.6), CaCl2 (10 mM), TCEP (0.5 mM), NaCl (50 mM), temperature not specified in the publication Homo sapiens N-{(2S)-1-amino-5-[(2-fluoroethanimidoyl)amino]-1-oxopentan-2-yl}benzamide
3.5.3.15 0.1
-
 in 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), dithiothreitol (2 mM) and NaCl (50 mM) at 37°C Homo sapiens chlortetracycline
3.5.3.15 0.4
-
 in 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), dithiothreitol (1 mM), at 37°C Homo sapiens N2-benzoyl-N5-(N,N-dimethylcarbamimidoyl)-L-ornithine
3.5.3.15 0.5
-
 IC50 above 0.5 mM, in 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), dithiothreitol (5 mM), at 37°C Homo sapiens 2-chloroacetamidine
3.5.3.15 0.78
-
 in 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), dithiothreitol (2 mM) and NaCl (50 mM) at 37°C Homo sapiens tetracycline
3.5.3.15 5
-
 IC50 is about 5 mM, at 52°C for 30 min in 50 mM HEPES (pH 7.6), CaCl2 (5 mM), dithiothreitol (2 mM) Homo sapiens paclitaxel

Expression

EC Number Organism Comment Expression
3.5.3.15 Homo sapiens camptothecin and staurosporine fail to stimulate PAD activity in HL-60 cells additional information
3.5.3.15 Homo sapiens PAD4 is elevated in patients with multiple sclerosis, ankylosing spondylitis, and osteoarthritis, and PAD4 levels are elevated in the blood of patients with malignant cancers up

General Information

EC Number General Information Comment Organism
3.5.3.15 physiological function PAD4 is involved in cellular differentiation, is a transcriptional corepressor for the estrogen receptor and p53 (deiminates the GRIP1 (glutamate receptor interacting protein 1) binding domain of p300, facilitating its interaction with GRIP1 and thus activating transcription), and is participated in NET formation. PAD4 influences gene expression through the deimination of histones H2A, H3 and H4. PAD4 downregulates the expression of p21, a cell cycle inhibitor, as well as PUMA and OKL38 (pregnancy-induced growth inhibitor), which are inducers of apoptosis. Increased PAD4 activity contributes to the onset and progression of rheumatoid arthritis Homo sapiens