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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase exists in interconvertible active and inactive forms in cultured fibroblasts from normal and familial hypercholesterolemic subjects. The inactive form can be activated by endogenous or added phosphoprotein phosphatase. Active or partially active HMG-CoA reductase in cell extracts was inactivated by a ATP-Mg-dependent reductase kinase. Incubation of phosphorylated (inactive) HMG-CoA reductase with purified phosphoprotein phosphatase was associated with dephosphorylation (reactivation) and complete restoration of HMG-CoA reductase activity. Low density lipoprotein, 25-hydroxycholesterol, 7-ketocholesterol, and mevalonolactone suppressed HMG-CoA reductase activity by a short-term mechanism involving reversible phosphorylation. 25-Hydroxycholesterol, which enters cells without the requirement of low density lipoprotein-receptor binding, inhibited the HMG-CoA reductase activity in familial hypercholesterolemic cells by reversible phosphorylation. Measurement of the short-term effects of inhibitors on the rate of cholesterol synthesis from radiolabeled acetate revealed that HMG-CoA reductase phosphorylation was responsible for rapid suppression of sterol synthesis. Reductase kinase activity of cultured fibroblasts was also affected by reversible phosphorylation. The active (phosphorylated) reductase kinase can be inactivated by dephosphorylation with phosphatase. Inactive reductase kinase can be reactivated by phosphorylation with ATP-Mg and a second protein kinase from rat liver, designated reductase kinase kinase. Reductase kinase kinase activity has been shown to be present in the extracts of cultured fibroblasts. The combined results represent the initial demonstration of a short-term regulation of HMG-CoA reductase activity and cholesterol synthesis in normal and receptor-negative cultured fibroblasts involving reversible phosphorylation of both HMG-CoA reductase and reductase kinase.
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PMID:Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts by reversible phosphorylation: modulation of enzymatic activity by low density lipoprotein, sterols, and mevalonolactone. 300 40

The reaction scheme of calcineurin was examined with kinetic and physical approaches. Proton inventory studies of the calcineurin-catalyzed hydrolysis of para-nitrophenyl phosphate were done to probe the role of proton transfer in the mechanism. Control experiments determined that the solvent did not cause the irreversible inactivation of the enzyme and had no effect on the dependence on metal ion or calmodulin. A solvent isotope effect was observed on the Vmax/Km term, but not the Vmax term. The isotope effect was modest with a value of 1.35. Proton inventory data could be fit by multiple parameter sets. The parameter sets yielded fractionation factors of 0.73 for a one-proton transfer or 0.85 for a two-proton transfer. These values compare to the value of 0.69 for reactions involving a water molecule or hydroxide coordinated to metal ion. A chemical mechanism consistent with the proton inventory data and other information about calcineurin catalysis is presented. The simplest model for catalysis involves a single proton transfer from water coordinated to metal that is reasoned to occur during association of the substrate with calcineurin. Questions about the reaction intermediate were also addressed. Attempts to monitor a phosphate-water exchange reaction with 31P nuclear magnetic resonance spectroscopy were unsuccessful. Failure to observe an exchange reaction suggests that no phosphoryl enzyme is formed during the progress of the reaction. Together these data are explained by a model in which cleavage of the phosphate ester bond is catalyzed by a water (hydroxide) molecule coordinated to a divalent metal ion without the formation of a covalent intermediate.
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PMID:Isotope effects on the mechanism of calcineurin catalysis: kinetic solvent isotope and isotope exchange studies. 818 43

Blockade of the mitochondrial permeability transition pore (mPTP) by cyclosporin A (CsA) inhibits apoptosis in various cell types. However, use of CsA in humans is associated with damage to the arterial endothelium. We evaluated whether inhibition of the apoptotic machinery by CsA promotes other forms of cell death in arterial endothelial cells (EC). Exposure of human umbilical artery EC (HUAEC) to clinically relevant concentrations of CsA for up to 24 h was associated with a significant increase in necrotic features. We detected inhibition of apoptosis and a significant increase in necrosis in HUAEC exposed concomitantly to CsA and mitomycin C, a proapoptotic DNA damaging agent. We found that CsA-induced cell death is independent of caspase activation, p53 induction, and calcineurin inhibition. However, bongkrekic acid, another mPTP blocker, also increased necrosis in HUAEC. Dihydroethidium and acridine orange staining revealed increased intracellular production of reactive oxygen species (ROS) followed by lysosomal damage in HUAEC exposed to CsA. Hydroxyl radical and superoxide scavengers and inhibition of cathepsin D activity significantly attenuated CsA-induced EC death. These results suggest that inhibition of the apoptotic machinery by CsA in arterial EC favors development of a necrotic form of cell death regulated by ROS and secondary lysosomal damage.
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PMID:Blockade of the apoptotic machinery by cyclosporin A redirects cell death toward necrosis in arterial endothelial cells: regulation by reactive oxygen species and cathepsin D. 1251 15

Rafter, Gale W. (The Johns Hopkins School of Medicine and School of Hygiene and Public Health, Baltimore, Md.) and William C. Lane. Phosphoproteins in Escherichia coli. J. Bacteriol. 83:1077-1083. 1962.-The identification and metabolism of phosphoprotein were investigated in Escherichia coli. Hydrolysis of bacterial protein fractions with barium hydroxide or with phosphoprotein phosphatase released acid-soluble phosphorus. Chromatography of acid-hydrolyzed and incubated fractions also indicated the presence of phospho-amino acids. Turnover of phosphate in protein of growing cells was not observed, but incorporation of phosphate into protein of nongrowing cells was found. The protein-phosphate content decreased as organisms passed from the growing to the nongrowing state. The phosphoprotein composition, as revealed by paper electrophoresis, was heterogeneous. No protein phosphokinase or protein-phosphate phosphatase was detected in cell-free extracts, but an active principle which catalyzed the formation of acid-soluble phosphate from bacterial protein fractions was found.
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PMID:Phosphoproteins in Escherichia coli. 1448 49

Cyanobacterial toxins (CBTs), produced by glue-green algae, are one of the most common naturally occurring toxins found in potable waters. The microcystin family of CBTs present in drinking water sources poses a considerable threat to human health. In this study, we have demonstrated that ultrasonic irradiation at 640 kHz leads to rapid degradation of microcystin-LR (MC-LR). Degradation of MC-LR present in the crude cyanobacterial extracts containing cell constituents has been studied with ultrasound under a variety of conditions. The degradation of MC-LR was demonstrated over a concentration range from 0.03 to 3.0 microM. Hydroxyl radical scavenger experiments indicate that hydroxyl radical is responsible for a significant fraction of the observed degradation, but other processes (hydrolysis/ pyrolysis) are also important. Analysis of the protein phosphatase inhibition activity of the reaction products indicates that the products from ultrasonic degradation of MC-LR do not exhibit any measurable biological activity. The results demonstrate that ultrasonic irradiation maybe an effective and practical method for the detoxification of microcystins from drinking water.
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PMID:Ultrasonically induced degradation and detoxification of microcystin-LR (cyanobacterial toxin). 1617 96

The cell-to-cell interaction through binding intercellular adhesion molecule (ICAM)-1 and CD40 on monocytes and their ligands such as lymphocyte function-associated antigen (LFA)-1 and CD40 ligand (CD40L) on T-cells plays roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, induces the expression of ICAM-1 and CD40 on monocytes, the production of interferon (IFN)-gamma and IL-12 and the proliferation of T-cells during the human mixed lymphocyte reaction (MLR). In addition to the cholesterol lowering effect, statins improve patient survival and decrease rejection episodes in transplant recipients. In the present study, we investigated the difference of effect of statins and calcineurin inhibitors during MLR. 3-Hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, fluvastatin and pravastatin and statin-derived LFA-1 inhibitors, LFA703 and LFA878, which did not inhibit HMG-CoA reductase, suppressed the production of IFN-gamma and IL-12 and the lymphocyte proliferation as well as the expression of ICAM-1 and CD40 on monocytes regardless of the presence of IL-18. However, the calcineurin inhibitors, tacrolimus and cyclosporine A (CsA), inhibited the IL-18-enhanced cytokine production and lymphocyte proliferation without any effect on the adhesion molecule expression. Thus, the action mechanism of stain is different from that of calcineurin inhibitors.
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PMID:Action profiles of statins and calcineurin inhibitors during human mixed lymphocyte reaction. 1748 16

Tinea incognito is the result of lack of diagnosis of dermatophyte infection of the glabrous skin and the misuse of steroids or calcineurin inhibitors. In this case report a 20-years-old female patient diagnosed as tinea incognito and Trichophyton rubrum isolated from her skin lesions, was presented. The patient suffered from an itchy skin lesion on her neck and right breast. Physical examination revealed and plaques with erythema and papules on neck and breast area. The patient had used several corticostero- ids suggested by dermatologists for 10 months. Direct microscopic examination of the skin scrapings with 10% potassium hydroxide preparation revealed fungal elements and Trichophyton rubrum was isolated in culture. Use of corticosteroids was ceased and terbinafine (250 mg tb and cream) therapy was initiated to continue for four weeks. Following treatment, total clinical and mycological cure was established. It was concluded that tinea incognito which was not a rare clinical entity, could be presented in various clinical forms and usually resulted from the wrong treatment modalities. Thus atypical erythematous plaques should be investigated in terms of presence of fungi and treated accordingly to establish total clinical and mycological cure.
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PMID:[A tinea incognito case caused by Trichophyton rubrum with clinical and mycological cure and review of the literature]. 2045 12

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