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Literature summary for 3.6.5.2 extracted from
- Role of small GTPase protein Rac1 in cardiovascular diseases: development of new selective pharmacological inhibitors (2013), J. Cardiovasc. Pharmacol., 62, 425-435.
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| angiotensin II | stimulates Rac1 as cardiovascular stimulus | Homo sapiens |  |
| endothelin-1 | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| Epidermal growth factor | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| GTP | the activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase activating proteins | Homo sapiens | |
| GTP | the activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase activating proteins. The activation process of Rac1 combines the GDP/GTP switch, catalyzed by GEF and GAP, with a cytosol/membrane alternation, regulated by GDI and protein prenylation, detailed overview | Homo sapiens | |
| guanine nucleotide exchange factors | GEF, GTP-binding to small GTPases is catalyzed by GEFs, Trp71 of Rac1 is a critical site for the discrimination of a subset of GEF, including Tiam1 and Trio | Homo sapiens | |
| Insulin-like growth factor | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| interleukin 1beta | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| lysophosphatidic acid | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| platelet-derived growth factor | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| Prorenin | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| sphingosine 1 phosphate | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| T-lymphoma invasion and metastasis factor 1 | Tiam1, a GEF, structure analysis in complex with Rac1, specific site of GEF-Rac1 interaction, in particular Trp71 | Homo sapiens | |
| thrombin | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| tumor necrosis factor-alpha | stimulates Rac1 as cardiovascular stimulus | Homo sapiens | |
| vascular endothelial growth factor | stimulates Rac1 as cardiovascular stimulus | Homo sapiens |
Application
| Application | Comment | Organism |
|---|---|---|
| pharmacology | the enzyme is a pharmacological target for the treatment of cardiovascular diseases | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| (2E)-2-[(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)methylidene][1,3]thiazolo[3,2-a]benzimidazol-3(2H)-one | inhibition of GEF-Rac1 interaction (selective for Trio) | Homo sapiens | |
| 2-(morpholin-4-ylmethyl)-5-[(5-[[7-(trifluoromethyl)quinolin-4-yl]sulfanyl]pentyl)oxy]-4H-pyran-4-one | inhibition of Rac1 nucleotide binding possiblly using an allosteric mechanism | Homo sapiens | |
| 2-amino-8-hydroxy-9-[3-hydroxy-2-(hydroxymethyl)cyclopentyl]-5,9-dihydro-6H-purin-6-one | inhibition of Rac1-dependent NADPH oxidase activity | Homo sapiens | |
| 3-(2-hydroxyphenyl)-N-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrazole-5-carboxamide | inhibition of GEF-Rac1 interaction (Tiam1, Trio, and Vav2), the compound inhibits lamellipodia formation and smooth muscle cell migration | Homo sapiens | |
| 9-methoxy-5-(3-nitrophenyl)-2-phenyl-3,10b-dihydropyrazolo[1,5-c][1,3]benzoxazine | inhibition of effector-Rac1 interaction (p67phox) | Homo sapiens | |
| GDP | the activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase activating proteins; the activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase activating proteins; the activation state of Rac1 depends on the release of guanosine diphosphate and the binding of guanosine triphosphate. This cycling is regulated by the guanine nucleotide exchange factors, as activators, and by the GTPase activating proteins | Homo sapiens | |
| additional information | three categories of selective Rac1 inhibitors affect different steps of the GTP/GDP pathway of enzyme activation: antagonists of Rac1-guanine nucleotide exchange factor interaction, allosteric inhibitors of nucleotide binding to Rac1, and antagonists of Rac1-mediated NADPH oxidase activity; three categories of selective Rac1 inhibitors affect different steps of the GTP/GDP pathway of enzyme activation: antagonists of Rac1-guanine nucleotide exchange factor interaction, allosteric inhibitors of nucleotide binding to Rac1, and antagonists of Rac1-mediated NADPH oxidase activity; three categories of selective Rac1 inhibitors affect different steps of the GTP/GDP pathway of enzyme activation: antagonists of Rac1-guanine nucleotide exchange factor interaction, allosteric inhibitors of nucleotide binding to Rac1, and antagonists of Rac1-mediated NADPH oxidase activity | Homo sapiens | |
| N-[4-methoxy-3-(piperidin-1-ylsulfonyl)phenyl]-1H-indazole-3-carboxamide | inhibition of GEF-Rac1 interaction (Tiam1) | Homo sapiens | |
| N4-(9-ethyl-9H-carbazol-3-yl)-N2-[3-(morpholin-4-yl)propyl]pyrimidine-2,4-diamine | inhibition of GEF-Rac1 interaction (selective for Vav2) | Homo sapiens | |
| N6-(2-[[5-(diethylamino)pentan-2-yl]amino]-6-methylpyrimidin-4-yl)-2-methylquinoline-4,6-diamine | a selective inhibitor for Rac1. The small molecule fits into the surface groove of Rac1 involved in the binding with GEFs, thus interfering with the Tiam1-Rac1 interaction | Homo sapiens | |
| statin | improves redox state in saphenous vein grafts in patients undergoing to coronary artery bypass grafting by inhibiting Rac1-mediated activation of NADPH oxidase | Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| plasma membrane | - |
Homo sapiens | 5886 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| GTP + H2O | Homo sapiens | - |
GDP + phosphate | - |
? | |
| additional information | Homo sapiens | at least 3 mitogen-activated protein kinases (MAPKs) are direct targets of Rac1: MLK2, MLK3, and MEKK4 | ? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P15153 | isozyme Rac2 | - |
| Homo sapiens | P60763 | isozyme Rac3 | - |
| Homo sapiens | P63000 | isozyme Rac1 | - |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| cardiomyocyte | - |
Homo sapiens | - |
| central nervous system | - |
Homo sapiens | - |
| endothelial cell | - |
Homo sapiens | - |
| heart | - |
Homo sapiens | - |
| hematopoietic cell | Rac2 is mainly present in the hematopoietic cells | Homo sapiens | - |
| leukocyte | - |
Homo sapiens | - |
| additional information | isozyme Rac1 is ubiquitous | Homo sapiens | - |
| smooth muscle cell | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| GTP + H2O | - |
Homo sapiens | GDP + phosphate | - |
? | |
| additional information | at least 3 mitogen-activated protein kinases (MAPKs) are direct targets of Rac1: MLK2, MLK3, and MEKK4 | Homo sapiens | ? | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| Rac1 | - |
Homo sapiens |
| Rac3 | - |
Homo sapiens |
| small GTPase | - |
Homo sapiens |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.0011 | - |
pH and temperature not specified in the publication | Homo sapiens | N4-(9-ethyl-9H-carbazol-3-yl)-N2-[3-(morpholin-4-yl)propyl]pyrimidine-2,4-diamine | |
| 0.005 | - |
pH and temperature not specified in the publication | Homo sapiens | 2-(morpholin-4-ylmethyl)-5-[(5-[[7-(trifluoromethyl)quinolin-4-yl]sulfanyl]pentyl)oxy]-4H-pyran-4-one | |
| 0.0087 | 0.0088 | pH and temperature not specified in the publication | Homo sapiens | 3-(2-hydroxyphenyl)-N-[4-(piperidin-1-ylsulfonyl)phenyl]-1H-pyrazole-5-carboxamide | |
| 0.01 | - |
pH and temperature not specified in the publication | Homo sapiens | 9-methoxy-5-(3-nitrophenyl)-2-phenyl-3,10b-dihydropyrazolo[1,5-c][1,3]benzoxazine | |
| 0.024 | - |
pH and temperature not specified in the publication | Homo sapiens | N-[4-methoxy-3-(piperidin-1-ylsulfonyl)phenyl]-1H-indazole-3-carboxamide | |
| 0.05 | - |
pH and temperature not specified in the publication | Homo sapiens | N6-(2-[[5-(diethylamino)pentan-2-yl]amino]-6-methylpyrimidin-4-yl)-2-methylquinoline-4,6-diamine | |
| 0.1 | - |
pH and temperature not specified in the publication | Homo sapiens | (2E)-2-[(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)methylidene][1,3]thiazolo[3,2-a]benzimidazol-3(2H)-one | |
| 0.156 | - |
pH and temperature not specified in the publication | Homo sapiens | 2-amino-8-hydroxy-9-[3-hydroxy-2-(hydroxymethyl)cyclopentyl]-5,9-dihydro-6H-purin-6-one | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | the enzyme belongs to the superfamily of small GTPase proteins | Homo sapiens |
| physiological function | Rac1 is one of the biologically important gene in coronary heart diseases. Rac directly regulates the activity of the NADPH oxidase and the generation of reactive oxygen species (ROS), important players of cardiovascular disorder | Homo sapiens |
| physiological function | Rac1 is one of the biologically important genes in coronary heart diseases, i.e. cardiomyocyte hypertrophy and atherosclerosis, overview. Rac directly regulates the activity of the NADPH oxidase and the generation of reactive oxygen species (ROS), important players of cardiovascular disorder. Rac1 facilitates the formation of the lamellipodia structures by initiating peripheral actin polymerization through the Arp2/3 complex that is activated by either the Wiskott-Aldrich syndrome protein (WASP) family or the WAVE (WASP with a V-domain) family proteins. Rac1, through the calmodulin-binding GAP, that is enriched at the leading edge of migrating cells, influences the organization of microtubules, and thus cell shape and polarity. In addition to the cytoskeletal and microtubules effects, Rac1 regulates several signal transduction pathways that lead to alterations in gene expression. Cellular effects of Rac1 activation in cardiomyocytes, smooth muscle cells, endothelial cells, and leukocytes, overview | Homo sapiens |
| physiological function | Rac1 is one of the biologically important genes in coronary heart diseases. Rac directly regulates the activity of the NADPH oxidase and the generation of reactive oxygen species (ROS), important players of cardiovascular disorder | Homo sapiens |
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