Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.25 (triphosphatase)
 1,529 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation of microbicidal oxidants by stimulated phagocytes is a major mechanism of host defence against infection and may also cause unwanted damage to host tissues in the setting of inappropriate inflammation. Recently, the molecular basis for oxidant production has been defined by elucidating the structure, biochemistry and regulation of the phagocyte NADPH oxidase, a multicomponent enzyme that uses NADPH to reduce molecular oxygen to superoxide anion which is then converted to hydrogen peroxide. Many of the advances resulted from the study of phagocytes obtained from patients with inherited abnormalities of the NADPH oxidase system, known as the chronic granulomatous diseases of childhood (CGD). These patients are susceptible to life-threatening infections. The NADPH oxidase is a complex enzyme system that has been shown to contain cytosolic and membrane components that assemble at the plasma membrane with cell activation. These components include a membrane NADPH-binding flavoprotein, cytochrome b558, the cytosolic proteins p47phox, p67phox and a small ras-related guanosine triphosphatase or rac protein that confers guanosine triphosphate sensitivity to the NADPH oxidase. Clinically, the NADPH oxidase system can be stimulated with interferon-gamma, resulting in reduced infections in patients with CGD. In addition, the recent incorporation of genes for the components of the NADPH oxidase into retrovirus vectors has resulted in successful transduction of these genes into blood stem cells from CGD patients with correction of the functional defect. This suggests that gene therapy for correction of CGD will be possible in the near future.
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PMID:Delineation of the phagocyte NADPH oxidase through studies of chronic granulomatous diseases of childhood. 818 51

T helper 1 (TH1) cells mediate cellular immunity, whereas TH2 cells potentiate antiparasite and humoral immunity. We used a complementary DNA subtraction method, representational display analysis, to show that the small guanosine triphosphatase Rac2 is expressed selectively in murine TH1 cells. Rac induces the interferon-gamma (IFN-gamma) promoter through cooperative activation of the nuclear factor kappa B and p38 mitogen-activated protein kinase pathways. Tetracycline-regulated transgenic mice expressing constitutively active Rac2 in T cells exhibited enhanced IFN-gamma production. Dominant-negative Rac inhibited IFN-gamma production in murine T cells. Moreover, T cells from Rac2-/- mice showed decreased IFN-gamma production under TH1 conditions in vitro. Thus, Rac2 activates TH1-specific signaling and IFN-gamma gene expression.
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PMID:Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. 1086 72

Recently, inhibitory cytokine pathways for leukocyte chemoattraction and activation have been identified, but there is little insight into the operational mechanisms except for models that rely on simple receptor antagonism. We have previously identified the existence of a murine eosinophil inhibitory pathway mediated by the CXC chemokine ligand 9 (CXCL9, Mig [monokine induced by interferon-gamma]) that impressively blocks eosinophil chemoattraction and function, but the mechanism has remained elusive. We now demonstrate that Mig's inhibitory action extends beyond receptor antagonism alone. Notably, in addition to inhibiting eotaxin-induced filamentous actin (F-actin) formation and chemoattraction, Mig potently blocks platelet activating factor (PAF)- and leukotriene B4 (LTB4)-induced responses. Remarkably, Mig-treated eosinophils display an abnormal F-actin assembly in the absence of agonist stimulation. Additionally, Mig pretreatment inhibits eotaxin-induced activation of the Rho-guanosine triphosphatase (GTPase) Rac, and Rac2-deficient eosinophils demonstrate an impaired transmigration and actin polymerization response to eotaxin stimulation. Furthermore, Mig was unable to inhibit eotaxin-induced responses in Rac2-deficient eosinophils. Finally, using CCR3 gene-targeted cells, Mig's inhibitory activity is demonstrated to be mediated by CC chemokine receptor 3 (CCR3). Thus, by altering agonist-induced signaling and abrogating cytoskeletal reorganization by a Rac2-dependent mechanism, Mig markedly inhibits eosinophil responses to diverse stimuli. These results establish evidence that distinct chemokines can use CCR3 to induce opposing signals in eosinophils.
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PMID:CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism. 1580 29