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)

A membrane fraction enriched in endoplasmic reticulum was prepared from rat parotid glands by using sucrose-gradient centrifugation. The fraction showed a 10-fold increase in specific activity of NADPH: cytochrome c reductase activity over that of tissue homogenates and minimal contamination with plasma membranes or mitochondria. The endoplasmic reticulum fraction possessed both Mg2+ -stimulated ATPase as well as Ca2+, Mg2+-ATPase [( Ca2+ + Mg2+)-stimulated ATPase]activity. The Ca2+, Mg2+-ATPase required 2-5 mM-Mg2+ for optimal activity and was stimulated by submicromolar concentrations of free Ca2+. The Km for free Ca2+ was 0.55 microM and the average Vmax. was 60 nmol/min per mg of protein. The Km for ATP was 0.11 mM. Other nucleotides, such as GTP, CTP or ADP, could not substitute for ATP in supporting the Ca2+-activated nucleotidase activity. Increasing the K+ concentration from 0 to 100 mM caused a 2-fold activation of the Ca2+, Mg2+-ATPase. Trifluoperazine, W7 [N-(6-aminohexyl)-5-chloronaphthalene-1-sulphonamide] and vanadate inhibited the enzyme. The concentration of trifluoperazine and vanadate required for 50% inhibition of the ATPase were 52 microM and 28 microM respectively. Calmodulin, cyclic AMP, cyclic AMP-dependent protein kinase and inositol 1,4,5-trisphosphate had no effect on the ATPase. The properties of the Ca2+, Mg2+ -ATPase were distinct from those of the Mg2+-ATPase, but comparable with those reported for the parotid endoplasmic-reticulum Ca2+-transport system [Kanagasuntheram & Teo (1982) Biochem. J. 208, 789-794]. The results suggest that the Ca2+, Mg2+-ATPase is responsible for driving the ATP-dependent Ca2+ accumulation by this membrane.
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PMID:The (Ca2+ + Mg2+)-stimulated ATPase of the rat parotid endoplasmic reticulum. 294 71

The mechanism involved in the stimulation of NADPH-oxidase by arachidonic acid (AA) in intact human neutrophils was studied and compared with that involved in a cell-free system. [3H]-AA was released from pre-labeled cells upon AA stimulation, and phospholipase A2 inhibitors reduced in parallel the release of [3H]-AA and superoxide. Cyclooxygenase, lipoxygenase or protein kinase inhibitors failed to affect either response. In a cell-free system, no release of [3H]-AA was observed after AA addition, whereas NADPH-oxidase was activated; the generation of superoxide was not inhibited by phospholipase inhibitors and was not initiated by adding phospholipase A2 to the preparation. Thus AA stimulates NADPH-oxidase through a phospholipase A2 mediated pathway in intact cells, but activates the oxidase independent of phospholipase A2 in a broken cell system, suggesting distinctive mechanisms of activation for each system.
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PMID:Activation of NADPH-oxidase by arachidonic acid involves phospholipase A2 in intact human neutrophils but not in the cell-free system. 301 32

The conversion of cholesterol to pregnenolone by adrenocortical mitochondria is the rate-limiting step in steroidogenesis. This process is stimulated dramatically by the action of ACTH through the sequential reactions, in which adenyl cyclase, cAMP-dependent protein kinase, cholesterol esterase and ribosomal protein synthesis are all involved. The de novo synthesized protein, the so-called labile protein with a half-life of approx 10 min, is believed to stimulate the cholesterol side chain cleavage reaction by an unknown mechanism. Available evidence indicates that the electron on transfer reaction from NADPH to P-450scc is mediated rapidly by adrenodoxin reductase and p-450 scc. In addition, these redox components are inactivated slowly with a half-life of 3.5 days after hypophysectomy. It is known that the corticoid output from adrenocortical cells starts within 5 min and reaches the maximum after 10-15 min of ACTH administration to animals. One can assume that under normal physiological conditions, both O2 and NADPH are not limiting. Additionally, mitochondrial inner membranes are poor in cholesterol. In this context, the availability of substrate cholesterol to P450scc is the most likely candidate for the regulatory mechanism.
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PMID:Transduction of ACTH signal from plasma membrane to mitochondria in adrenocortical steroidogenesis. Effects of peptide, phospholipid, and calcium. 302 55

Addition of the chemotactic peptide, f-Met-Leu-Phe, to human monocytes induced a burst of superoxide release, which ceased after approximately 3 min. Diminished responsiveness to f-Met-Leu-Phe, but not to phorbol myristate acetate (PMA), was induced by 1- to 3-h storage at 0 degrees C or by 2 min in 40 microM adenosine (ADO). Reversal of the ADO block was achieved by addition of adenosine deaminase (ADA) as little as 15 sec before the f-Met-Leu-Phe stimulus; ADA had no effect when added poststimulus. The ADO experiments suggest that there are a minimum of two sequentially produced intermediates in the f-Met-Leu-Phe stimulus-response pathway. The first intermediate persists for less than 30 sec. The second, formation of which is stimulated by the first, persists for the duration of the response and is the target of ADO inhibition. The ADO target is apparently not protein kinase-C, since the response of inhibited cells to PMA was unimpaired. The maximal inhibition by adenosine of f-Met-Leu-Phe-induced superoxide generation was approximately 50%. It is possible that f-Met-Leu-Phe stimulates two pathways of NADPH activation, only one of which is inhibited by adenosine.
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PMID:Dynamics of chemotactic peptide-induced superoxide generation by human monocytes. 303 84

We have reported previously that calcium ions and phospholipid activate the heme-stabilized proinhibitor form (pro-HCI) of the heme-controlled translational inhibitor (HCI) in reticulocyte lysates and promote the first step of the reaction pro-HCI in equilibrium reversible HCI----irreversible HCI. This suggested the possible involvement of a Ca2+/phospholipid-dependent protein kinase (protein kinase C) in the activation. However, further investigation revealed, among other things, that polyunsaturated fatty acids (e.g., arachidonic acid) were as effective as Ca2+/phospholipid in promoting translational inhibition and phosphorylation of the alpha subunit of the chain-initiation factor eIF-2 and, moreover, HCI activation could be prevented or reversed in either case by NADPH-generating systems or by dithiols. Our results suggest that pro-HCI is activated by lipoperoxides produced in reticulocyte lysates from either phospholipid or polyunsaturated fatty acids; the presence of Ca2+ is required in the former but not in the latter case. The reversible activation of HCI by Ca2+ and phospholipid might suggest a possible modulatory role of Ca2+ in translational control.
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PMID:Mechanism of activation of the heme-stabilized translational inhibitor of reticulocyte lysates by calcium ions and phospholipid. 315 12

Thylakoid protein phosphorylation was facilitated in darkness by using the ferredoxin-NADPH system. CoCl2 and DBMIB (2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone) were potent inhibitors of LHCP (light-harvesting chlorophyll-binding protein) phosphorylation, but 3-(3,4-dichlorophenyl)-1,1-dimethyl-urea and atrazine had no significant effect. Differential effects on phosphorylation of the 9 kDa polypeptide and LHCP were observed in darkness with DBMIB and certain other inhibitors specific for Photosystem-II electron transport. Similarly, during illumination of intact chloroplasts or of the reconstituted chloroplast system, a differential action of bicarbonate was observed on the relative phosphorylation of the two proteins. The degree of phosphorylation of the 9 kDa polypeptide was increased in the presence of bicarbonate compared with its absence, whereas that of LHCP was relatively unchanged. Changes in the degree of phosphorylation of the 32 kDa polypeptide in these experiments did not correlate consistently with changes in phosphorylation of either LHCP or the 9 kDa polypeptide, although changes in the 32 kDa polypeptide more often paralleled phosphorylation of the 9 kDa polypeptide rather than the phosphorylation of LHCP. These observations suggest that the protein kinase that phosphorylates LHCP is distinct from that which phosphorylates the 9 kDa polypeptide.
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PMID:Evidence for different kinases in thylakoid protein phosphorylation. 332 34

We have demonstrated that the purified guanine nine nucleotide exchange factor (GEF) may be isolated as a complex with NADPH. Complete inhibition of the GEF-catalyzed exchange of eukaryotic initiation factor 2-bound GDP for GTP was observed in the presence of either 0.5-0.75 mM NAD+ or NADP+. Incubation of GEF with ATP results in the phosphorylation of its Mr 82,000 polypeptide. This phosphorylation is strongly inhibited by heparin but is not affected by heme or H8 (N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of cAMP- and cGMP-dependent protein kinases and protein kinase C. The purification of GEF was modified to eliminate any contaminating kinase activity and the isolated protein appears to be homogeneous as judged by NaDodSO4/polyacrylamide gel electrophoresis and silver staining. The Mr 82,000 subunit of GEF is phosphorylated only upon addition of ATP and casein kinase II. The extent of phosphorylation is approximately equal to 0.55 mol of phosphate per mol of GEF, and this results in a 2.3-fold increase in the guanine nucleotide exchange activity. Following treatment of the phosphorylated GEF with alkaline phosphatase, the activity of the protein is reduced by a factor of 5. Rephosphorylation of GEF increases its specific activity to that of the phosphorylated protein. The results of this study suggest that phosphorylation/dephosphorylation of GEF plays a role in regulating polypeptide chain initiation.
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PMID:Phosphorylation of the guanine nucleotide exchange factor from rabbit reticulocytes regulates its activity in polypeptide chain initiation. 342 26

The synthesis of globin, the major protein synthesized by reticulocytes, requires the presence of heme, the prosthetic group of hemoglobin. The absence of heme leads to the activation of a nucleotide-independent protein kinase that phosphorylates the alpha subunit of the chain initiation factor eIF-2. This modification interferes with the catalytic function of eIF-2 in protein synthesis initiation. Recent progress in our understanding of the molecular mechanism of this inhibition is briefly reviewed. The same phosphorylation is catalyzed by a different enzyme (DAI) which, while constitutive in reticulocytes, is induced by interferon in other cells. This enzyme is activated by low concentrations of double-stranded RNA in conjunction with ATP. The mechanisms of activation of these enzymes are still poorly understood. HCI is believed to form an inactive complex with heme and become active when the heme is removed by hemoglobin formation. The proinhibitor form of HCI (proHCI) is unstable in vitro and, even in the presence of heme, is irreversibly inactivated by SH-binding reagents, alkaline pH, slightly elevated temperatures, or high hydrostatic pressure. In hemin-supplemented reticulocyte lysates proHCI can also be reversibly activated by oxidized glutathione (GSSG) or NADPH depletion as well as by polyunsaturated fatty acids and by Ca2+-phospholipid. The mechanism of activation of HCI by GSSG has not been clarified although it appears to involve oxidation of proHCI SH groups to disulfides. Like activation by GSSG, the activation of HCI by polyunsaturated fatty acids and by Ca2+-phospholipid also appears to be largely due to oxidation of some of the enzyme's SH groups. There thus appear to be two fully independent mechanisms of HCI activation in reticulocyte lysates, one involving heme deficiency, the other involving oxidation of proHCI SH groups. The latter, but not the former, can be prevented or reversed by NADPH generators or dithiols. ProHCI appears to be maintained in the reduced, inactive state by a system involving NADPH, thioredoxin, and thioredoxin reductase.
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PMID:Protein phosphorylation and translational control in reticulocytes: activation of the heme-controlled translational inhibitor by calcium ions and phospholipid. 409 99

The models proposed for the means whereby the B-cell recognises glucose and related compounds as signals for insulin release and biosynthesis are discussed. The observed correlations between rates of metabolism and insulin release and biosynthesis are consistent with the substrate-site hypothesis. For glucose itself, the enzymes catalysing the phosphorylation of the sugar provide an explanation for the major characteristics of the islet responses, but for N-acetylglucosamine evidence is presented that the sugar transport system fulfils this discriminatory role. Possible mechanisms whereby sugar metabolism may be linked to changes in Ca2+-handling are considered and evidence is given supporting a role for the cytosolic NADPH/NADP+ ratio and the islet content of phosphoenolpyruvate. The nature of the targets for cyclic AMP and Ca2+ is discussed and some properties of islet cAMP-dependent protein kinase are summarised. Evidence is presented for the presence of calmodulin in islets and the possible involvement of calmodulin in stimulus-secretion coupling. On the basis of these considerations a speculative hypothesis for the mechanisms involved in the B-cell responses to glucose is outlined.
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PMID:Glucoreceptor mechanisms and the control of insulin release and biosynthesis. 624 6

Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.
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PMID:Cholesterol metabolism in the adrenal cortex. 631 Feb 52


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