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Literature summary for 3.5.3.15 extracted from
- Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential (2009), Curr. Opin. Drug Discov. Devel., 12, 616-627.
Application
| Application | Comment | Organism |
|---|---|---|
| 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
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 2-chloroacetamidine | - |
Homo sapiens |  |
| chlortetracycline | - |
Homo sapiens | |
| Cl-amidine | highly potent PAD4 inactivator, inactivates the enzyme via the alkylation of Cys645 | Homo sapiens | |
| F-amidine | highly potent PAD4 inactivator, inactivates the enzyme via the alkylation of Cys645 | Homo sapiens | |
| N-{(2S)-1-amino-5-[(2-chloroethanimidoyl)amino]-1-oxopentan-2-yl}benzamide | - |
Homo sapiens | |
| N-{(2S)-1-amino-5-[(2-fluoroethanimidoyl)amino]-1-oxopentan-2-yl}benzamide | - |
Homo sapiens | |
| N2-benzoyl-N5-(N,N-dimethylcarbamimidoyl)-L-ornithine | inhibits PAD4 at high micromolar to millimolar concentrations | Homo sapiens | |
| paclitaxel | inhibits PAD4 at high micromolar to millimolar concentrations | Homo sapiens | |
| tetracycline | - |
Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytoplasmic vesicle | - |
Homo sapiens | 31410 | - |
| nucleus | - |
Homo sapiens | 5634 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| 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)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| protein L-Arg + H2O | Homo sapiens | - |
protein citrulline + NH3 | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
- |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| A-549 cell | - |
Homo sapiens | - |
| bladder carcinoma cell | - |
Homo sapiens | - |
| breast adenocarcinoma cell | - |
Homo sapiens | - |
| chondroma cell | - |
Homo sapiens | - |
| colorectal adenocarcinoma cell | - |
Homo sapiens | - |
| endometrial carcinoma cell | - |
Homo sapiens | - |
| eosinophil | - |
Homo sapiens | - |
| esophageal squamous cell carcinoma cell | - |
Homo sapiens | - |
| granulocyte | - |
Homo sapiens | - |
| hepatocellular carcinoma cell | - |
Homo sapiens | - |
| lung adenocarcinoma cell | - |
Homo sapiens | - |
| macrophage | - |
Homo sapiens | - |
| MCF-7 cell | - |
Homo sapiens | - |
| neutrophil | - |
Homo sapiens | - |
| ovarian cancer cell | - |
Homo sapiens | - |
| renal cancer cell | - |
Homo sapiens | - |
| SKOV-3 cell | - |
Homo sapiens | - |
| U-937 cell | - |
Homo sapiens | - |
| uterine adenocarcinoma cell | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| benzoyl-L-arginine amide + H2O | best small-molecule substrate for PAD4 | Homo sapiens | ? | - |
? | |
| histone H2A-L-arginine + H2O | - |
Homo sapiens | histone H2A-L-citrulline + NH3 | - |
? | |
| histone H3-L-arginine + H2O | - |
Homo sapiens | histone H3-L-citrulline + NH3 | - |
? | |
| histone H4-L-arginine + H2O | - |
Homo sapiens | histone H4-L-citrulline + NH3 | - |
? | |
| p300-L-arginine + H2O | - |
Homo sapiens | ? | - |
? | |
| protein L-Arg + H2O | - |
Homo sapiens | protein citrulline + NH3 | - |
? | |
| vimentin-L-arginine + H2O | - |
Homo sapiens | vimentin-L-citrulline + NH3 | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| PAD4 | isozyme | Homo sapiens |
| protein arginine deiminase 4 | isozyme | Homo sapiens |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 7.6 | - |
- |
Homo sapiens |
Ki Value [mM]
| Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 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 | |
| 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 | |
| 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
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | camptothecin and staurosporine fail to stimulate PAD activity in HL-60 cells | additional information |
| 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
| General Information | Comment | Organism |
|---|---|---|
| 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 |
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