Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indoleamine 2, 3-dioxygenase (IDO), a key enzyme that catalyses the initial and rate-limiting step in the degradation of the tryptophan, is simultaneously expressed in murine dendritic cells and macrophages stimulated with interferon-gamma (IFN-gamma). In the present study, we investigated whether p-Coumaric acid (CA), which is suggested to exhibit antioxidant properties, could suppress the functional expression of IDO in murine bone marrow-derived dendritic cells (BMDCs) stimulated with IFN-gamma. Treatment with CA reduced intracellular expression of IDO mRNA and protein levels in IFN-gamma-activated murine BMDCs in vitro and in CD11c(+)CD8alpha(+) DCs of tumor-draining lymph node (TDLN) of tumor-bearing mice in vivo. Consequently, we obtained evidence that CA suppresses the functional activity of IDO, which catalyses oxidative catabolism of tryptophan, and significantly recovers the IDO-dependent T cell suppression. Activation of the signal transducer and activator of transcription 1 (STAT1) is important to be express IDO in IFN-gamma-stimulated murine BMDCs. To determine whether these inhibitory effects of CA are associated with the alteration of the signal transducer and activator of transcription 1 (STAT1) and IFN-gamma-inducible, dsRNA-activated serine/threonine protein kinase (PKR), BMDCs were pretreated with various concentrations of CA. We found that CA inhibited the activation of STAT1 in response to IFN-gamma. Based on our results, this study may account that CA could inhibit IDO expression by down-regulation of STAT1 activation in IFN-gamma-stimulated murine DCs.
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PMID:p-Coumaric acid inhibits indoleamine 2, 3-dioxygenase expression in murine dendritic cells. 1746 14

The sterile alpha motifs or SAM domains are small ( approximately 70 amino acids) protein-protein interaction modules that are involved in diverse functions ranging from cell signaling, transcription regulation, and scaffolding. The Ste11 protein kinase in the mitogen-activated protein kinase (MAPK) signaling cascades of the budding yeast is regulated by a SAM domain located at the N-terminus of the full-length protein. The Ste11 SAM domain forms a symmetrical dimeric structure with an interface stabilized presumably by hydrophobic and ionic interactions. Here, we investigated urea-induced unfolding, using NMR and other optical spectroscopic methods, of the dimeric Ste11 SAM domain and two of the variants, namely, L57R and L60R, each containing a point mutation at the interfacial region. Our results demonstrate that the residue-specific or global unfolding of the Ste11 SAM is highly cooperative without any evidence for folded monomeric or partially folded species. However, replacement of hydrophobic residues with basic residues in the interface caused considerable changes in the stability and folding of the Ste11 SAM domain. The native dimeric structure of the L60R mutant protein is severely affected as indicated by a high propensity toward aggregation. On the other hand, the L57R mutant, although retaining the native structure, shows a dramatic decrease in the conformational stability as revealed by urea-induced denaturation and amide proton exchange studies. Furthermore, isothermal titration calorimetry and intrinsic tryptophan fluorescence experiments demonstrate that the L57R interacts with the cognate SAM domain from Ste50 with reduced affinity, while the L60R protein is devoid of any detectable binding activity. These results demonstrate that the interfacial residues of the dimeric SAM domain of Ste11 are critically involved in its structural stability and binding to the Ste50 SAM domain.
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PMID:Equilibrium unfolding of the dimeric SAM domain of MAPKKK Ste11 from the budding yeast: role of the interfacial residues in structural stability and binding. 1809 17

Human small heat shock protein with molecular mass 22 kD (HSP22, HspB8) contains two Ser residues (Ser24 and Ser57) in consensus sequence RXS and is effectively phosphorylated by cAMP-dependent protein kinase in vitro. Mutation S24D did not affect, whereas mutations S57D or S24,57D prevented phosphorylation of HSP22 by cAMP-dependent protein kinase thus indicating that Ser57 is the primary site of phosphorylation. Phosphorylation (or mutation) of Ser57 (or Ser24 and Ser57) resulted in changes of the local environment of tryptophan residues and increased HSP22 susceptibility to chymotrypsinolysis. Mutations mimicking phosphorylation decreased dissociation of HSP22 oligomer at low concentration without affecting its quaternary structure at high protein concentration. Mutations S24D, S57D, and especially S24,57D were accompanied by decrease of chaperone-like activity of HSP22 if insulin and rhodanase were used as substrates. Thus, phosphorylation by cAMP-dependent protein kinase affects the structure and decreases chaperone-like activity of HSP22 in vitro.
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PMID:Phosphorylation by cyclic AMP-dependent protein kinase inhibits chaperone-like activity of human HSP22 in vitro. 1829 77

We describe a novel aspect of action of memantine ex vivo, in the brain cortical slices and in vitro, in mixed glial cultures. The drug potently increased the production of kynurenic acid, an endogenous tryptophan metabolite blocking N-methyl-D-aspartate (NMDA) and nicotinic alpha7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100-150 microM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of kynurenic acid. Neither SCH23390, D1 receptor antagonist (50 microM) nor raclopride, D2 receptor antagonist (10 microM) changed the memantine-induced effects. Propranolol (100 microM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 microM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 microM) totally reversed the action of memantine. In mixed glial cultures, 2-24 h incubation with memantine (2-50 microM) enhanced the production of kynurenic acid. Memantine (up to 0.5 mM) has not affected the activity of kynurenic acid biosynthetic enzymes. The obtained data suggest that memantine enhances the production of kynurenic acid in PKA-mediated way. This effect may partially contribute to the therapeutic actions of memantine and be of a potential clinical importance.
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PMID:Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism. 1834 50

Protein kinase B (PKB)/Akt has been strongly implicated in the insulin-dependent stimulation of GLUT4 translocation and glucose transport in skeletal muscle and fat cells. Recently an allosteric inhibitor of PKB (Akti) that selectively targets PKBalpha and -beta was reported, but as yet its precise mechanism of action or ability to suppress key insulin-regulated events such as glucose and amino acid uptake and glycogen synthesis in muscle cells has not been reported. We show here that Akti ablates the insulin-dependent regulation of these processes in L6 myotubes at submicromolar concentrations and that inhibition correlates tightly with loss of PKB activation/phosphorylation. Similar findings were obtained using 3T3-L1 adipocytes. Akti did not inhibit IRS1 tyrosine phosphorylation, phosphatidylinositol 3-kinase signaling, or activation of Erks, ribosomal S6 kinase, or atypical protein kinases C but significantly impaired regulation of downstream PKB targets glycogen synthase kinase-3 and AS160. Akti-mediated inhibition of PKB requires an intact kinase pleckstrin homology domain but does not involve suppression of 3-phosphoinositide binding to this domain. Importantly, we have discovered that Akti inhibition is critically dependent upon a solvent-exposed tryptophan residue (Trp-80) that is present within the pleckstrin homology domain of all three PKB isoforms and whose mutation to an alanine (PKB(W80A)) yields an Akti-resistant kinase. Cellular expression of PKB(W80A) antagonized the Akti-mediated inhibition of glucose and amino acid uptake. Our findings support a critical role for PKB in the hormonal regulation of glucose and system A amino acid uptake and indicate that use of Akti and expression of the drug-resistant kinase will be valuable tools in delineating cellular PKB functions.
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PMID:Use of Akt inhibitor and a drug-resistant mutant validates a critical role for protein kinase B/Akt in the insulin-dependent regulation of glucose and system A amino acid uptake. 1866 36

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step in the degradation of tryptophan and is strongly induced in interferon-gamma (IFNgamma)-stimulated dendritic cells (DCs). IDO has recently been established as a key enzyme in T-cell suppression-mediated immune tolerance to tumors. STAT1 phosphorylation appears to play an important role in the control of IDO expression by IFNgamma, but the precise regulatory mechanism remains obscure. Here we present a novel mechanism of IFNgamma-induced IDO expression in bone marrow-derived dendritic cells. In addition, we demonstrate that curcumin, an active component of turmeric, significantly inhibited the induction of IDO expression and activity by IFNgamma. We found that curcumin suppressed STAT1 activation by directly inhibiting Janus-activated kinase 1/2 and protein kinase Cdelta phosphorylation in bone marrow-derived DCs, suppressing the subsequent translocation and binding of STAT1 to the GAS element of the IRF-1 promoter. Coincident with these inhibitory effects on IFNgamma-induced IDO expression, curcumin reversed IDO-mediated suppression of T-cell responses. Our results, thus, suggest that down-regulation of IDO in DCs is an important immunomodulatory property of curcumin that may be exploited therapeutically in the control of cancers.
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PMID:Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. 1907 17

In Chinese hamster ovary cells expressing rabbit sodium-dependent glucose transporter (rbSGLT1) protein kinase A (PKA) activators (forskolin and 8-Br-cAMP) stimulated alpha-methyl D-glucopyranoside uptake. Kinetic analysis revealed an increase in both V(max) and affinity of the transport. Immunohistochemistry and biotinylation experiments showed that this stimulation was accompanied by an increased amount of SGLT1 localized into the plasma membrane, which explains the higher V(max) of the transport. Cytochalasin D only partly attenuated the effect of forskolin as did deletion of the PKA phosphorylation site of SGLT1 in transient transfection studies. Experiments using an anti-phosphopeptide antibody revealed that forskolin also increased the extent of phosphorylation of SGLT1 in the membrane fraction. These results suggested that regulation of SGLT1 mediated glucose transport involves an additional direct effect on SGLT1 by phosphorylation. To evaluate this assumption further, phosphorylation studies of recombinant human SGLT1 (hSGLT1) in vitro were performed. In the presence of the catalytic subunit PKA and [(32)P] ATP 1.05 mol of phosphate were incorporated/mol of hSGLT1. Additionally, phosphorylated hSGLT1 demonstrated a reduction in tryptophan fluorescence intensity and a higher quenching by the hydrophilic Trp quencher acrylamide, particularly in the presence of D-glucose. These results indicate that PKA-mediated phosphorylation of SGLT1 changes the conformation of the empty carrier and the glucose carrier complex, probably causing the increase in transport affinity. Thus, PKA-mediated phosphorylation of the transporter represents a further mechanism in the regulation of SGLT1-mediated glucose transport in epithelial cells, in addition to a change in surface membrane expression.
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PMID:Protein kinase-A affects sorting and conformation of the sodium-dependent glucose co-transporter SGLT1. 1911 53

Mesenchymal stem cells (MSC) display unique suppressive properties on T-cell immunity, thus representing an attractive vehicle for the treatment of conditions associated with harmful T-cell responses such as organ-specific autoimmunity and graft-versus-host disease. Toll-like receptors (TLR) are primarily expressed on antigen-presenting cells and recognize conserved pathogen-derived components. Ligation of TLR activates multiple innate and adaptive immune response pathways to eliminate and protect against invading pathogens. In this work, we show that TLR expressed on human bone marrow-derived MSC enhanced the immunosuppressive phenotype of MSC. Immunosuppression mediated by TLR was dependent on the production of immunosuppressive kynurenines by the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase-1 (IDO1). Induction of IDO1 by TLR involved an autocrine interferon (IFN)-beta signaling loop, which was dependent on protein kinase R (PKR), but independent of IFN-gamma. These data define a new role for TLR in MSC immunobiology, which is to augment the immunosuppressive properties of MSC in the absence of IFN-gamma rather than inducing proinflammatory immune response pathways. PKR and IFN-beta play a central, previously unidentified role in orchestrating the production of immunosuppressive kynurenines by MSC.
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PMID:Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R. 1935 19

The central levels of endogenous tryptophan metabolite kynurenic acid (KYNA), an antagonist of N-methyl-d-aspartate (NMDA) and alpha7-nicotinic receptors, affect glutamatergic and dopaminergic neurotransmission. Here, we demonstrate that selective agonists of beta(1)-receptors (xamoterol and denopamine), beta(2)-receptors (formoterol and albuterol), alpha- and beta-receptors (epinephrine), 8pCPT-cAMP and 8-Br-cAMP (analogues of cAMP) increase the production of KYNA in rat brain cortical slices and in mixed glial cultures. Neither betaxolol, beta(1)-adrenergic antagonist, nor timolol, a non-selective beta(1,2)-adrenergic antagonist has influenced synthesis of KYNA in both paradigms. In contrast, KT5720, a selective inhibitor of protein kinase A (PKA), strongly reduced KYNA formation in cortical slices (2-10 microM) and in glial cultures (100 nM). beta-adrenergic antagonists and KT5720 prevented the beta-adrenoceptor agonists-induced increases of KYNA synthesis. In vivo, beta-adrenergic agonist clenbuterol (0.1-1.0 mg/kg) increased the cortical endogenous level of KYNA; the effect was blocked with propranolol (10 mg/kg). beta-adrenoceptors agonists, cAMP analogues and KT5720 did not affect directly the activity of KAT I or KAT II measured in partially purified cortical homogenate. In contrast, the exposure of intact cultured glial cells to pCPT-cAMP, 8-Br-cAMP and formoterol has lead to an enhanced action of KATs. These findings demonstrate that beta-adrenoceptor-mediated enhancement of KYNA production is a cAMP- and PKA-dependent event. PKA activity appears to be an essential signal affecting KYNA formation. Described here novel mechanism regulating KYNA availability may be of a potential importance, considering that various stimuli, among them clinically used drugs, activate cAMP/PKA pathway, and thus could counteract the central deficits of KYNA.
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PMID:beta-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling. 1943 40

The wound-healing properties of honey are well established and it has been suggested that, among its pharmaco-active constituents, kynurenic acid (KA) exerts antinociceptive action on injured tissue by antagonizing NMDA at peripheral GABA receptors. The aim of this study was to investigate the quantitative profile of KA and of two recently identified, structurally related derivatives, 3-pyrrolidinyl-kynurenic acid (3-PKA) and its gamma-lactamic derivative (gamma-LACT-3-PKA), by examining their mass spectrometric behavior, in honeys from different botanical sources. We used a combination of HPLC-DAD-ESI-MS and NMR techniques (one-dimensional (1)H NMR and diffusion-ordered spectroscopy NMR). Chestnut honey constantly contained KA (2114.9-23 g/kg), 3-PKA (482.8-80 mg/kg) and gamma-LACT-3-PKA (845.8-32 mg/kg), confirming their reliability as markers of origin. A new metabolite, 4-quinolone (4-QUIN), was identified for the first time in one chestnut honey sample (743.4 mg/kg). Small amounts of KA were found in honeydew, sunflower, multifloral, almond and eucalyptus honeys, in the range of 23.1-143 mg/kg, suggesting contamination with chestnut honey. Total phenol content (TPC) was in the range from 194.9 to 1636.3 mg(GAE)/kg and total antiradical activity (TAA) from 61 to 940 mg/(GAE)/kg), depending on the botanical origin. Principal component analysis (PCA) was then done on these data. The three different clusters depicted: (i) antinociceptive activity from KA and/or its derivatives, typical of chestnut honey; (ii) antioxidant/radical scavenging activity by antioxidants responsible for the antiinflammatory action (dark honeys); (iii) peroxide-dependent antibacterial activity due to H(2)O(2) production by glucose oxidase in honey. The PCA findings provide useful indications for the dermatologist for the treatment of topical diseases, and the profiling of KA and its derivatives may shed light on new aspects of the kynurenine pathway involved in tryptophan metabolism.
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PMID:Quinoline alkaloids in honey: further analytical (HPLC-DAD-ESI-MS, multidimensional diffusion-ordered NMR spectroscopy), theoretical and chemometric studies. 1956 Mar 2


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