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)

A number of protein modification activities are present in the protein-synthesizing complex isolated from rabbit reticulocytes. These enzymes are solubilized by sedimentation of the ribosomes through buffered sucrose containing 0.5 M KCl, and have been partially purified from the high salt wash fraction by chromatography on DEAE-cellulose and phosphocellulose. The ribosomal-associated enzymatic activities include cyclic AMP-regulated and cyclic nucloetide-independent protein kinase, phosphoprotein phosphatase, and acetyltransferase activities. These enzymatic activities have been shown to modify specific ribosomal and ribosomal-associated proteins. The cycli c AMP-regulated protein kinase phosphorylate the 40 S ribosomal subunit from rabbit reticulocytes. One of the cyclic nucleotide-independent protein kinase catalyzes the phosphorylation of two different factors involved in the initiation of hemoglobin synthesis. A single phosphoprotein phosphatase activity is shown to remove phosphate from 40 S ribosomal subunits. The major acetyltransferase activity associated with ribosomes acetylates a 60 S ribosomal protein.
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PMID:Protein modification enzymes associated with the protein-synthesizing complex from rabbit reticulocytes. Protein kinase, phosphoprotein phosphatase, and acetyltransferase. 1 14

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) synthesized by bovine aortic endothelial cells and subcellular fractions thereof was assayed by its stimulating effect on soluble guanylyl cyclase of rat fetal lung fibroblasts (RFL-6 cells). The release of EDRF/NO by intact endothelial cells could be stimulated with bradykinin, thrombin, or ADP and was abolished in Ca2(+)-free medium. When subcellular fractions were analyzed, some EDRF/NO-synthesizing activity was found in the cytosolic fraction, but most of the activity was associated with the particulate fraction. Both enzyme activities required L-arginine and NADPH for EDRF/NO synthesis, both were inhibited by NG-nitro-L-arginine and NG-methyl-L-arginine, and hemoglobin or methylene blue abolished the effect of the EDRF/NO produced by both enzymes. Both enzymes were highly sensitive to Ca2+; the major increase in activity occurred between 100 and 500 nM free Ca2+. Exposure of the particulate enzyme activity to 1 M KCl removed 39% of the protein and reduced total activity by 46%, but the activity was restored when exogenous calmodulin (CaM) was added. Further KCl washes caused little further loss of protein or EDRF/NO synthase activity. The KCl-washed particulate enzyme could be solubilized with the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. The CaM antagonists calmidazolium and trifluoperazine as well as the CaM-binding protein calcineurin inhibited the EDRF/NO synthesis by both the cytosolic and the particulate enzyme. These effects were partially reversed with exogenous CaM. Partial purification of the cytosolic and solubilized particulate enzymes by affinity chromatography on adenosine 2',5'-bisphosphate-Sepharose resulted in EDRF/NO synthase activities dependent on exogenous CaM. We conclude that endothelial cells contain both cytosolic and particulate enzymes that synthesize EDRF/NO. Both enzymes are regulated by free Ca2+ and, at least in part, by CaM.
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PMID:Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells. 170 8

More than 97% of spectrin phosphatase activity in human erythrocyte hemolysate was recovered in cytosol. The cytosolic phosphatase activity was resolved into four peaks, namely phosphatases I (22%, Mr = 180,000), II (3%, Mr = 42,000), III (8%, Mr = 177,000), and IV (62%, Mr = 104,000), by aminohexyl-Sepharose column chromatography. Although these phosphoprotein phosphatases also catalyzed the dephosphorylation of phosphorylase a, glycogen synthase b, and phosphorylated H1 and H2B histones, the phosphatases differed from each other in preferences for substrates and the Mg2+ or Mn2+ requirements for their activities. The treatment with 80% ethanol converted phosphatases I, III, and IV to Mr = 31,000 forms which had essentially the same physical and catalytic properties. By contrast, the molecular weight and catalytic properties of phosphatase II, which was Mg2+- or Mn2+-dependent, were not changed by the same ethanol treatment. The major spectrin phosphatase, phosphatase IV, was purified to near homogeneity, as judged by polyacrylamide gel electrophoresis. Sodium dodecyl sulfate-gel electrophoresis revealed that the enzyme was composed of one 32,000-Da polypeptide (alpha) and one 69,000-Da polypeptide (beta). Km values of the enzyme for phosphorylated spectrin and H2B histone were 1.63 +/- 0.45 and 48.2 +/- 7.6 microM, respectively. The spectrin phosphatase activity was stimulated about 2-fold by 5-25 mM Mg2+, but was completely inhibited by the same concentration of Mn2+. Physiological concentrations of adenine nucleotides, 2,3-diphosphoglyceric acid, cyclic nucleotides, or Ca2+ and/or calmodulin had no significant effect on the reaction, but 20 mg/ml of hemoglobin inhibited the reaction by 60%. -SH-blocking agents but not iodoacetate inhibited the reaction.
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PMID:Phosphoprotein phosphatases in human erythrocyte cytosol. 630 5

A discontinuous structure-activity relationship signaled a change in mode of action and led to the discovery of a possible novel metabolic activation mechanism. The toxicity of the herbicide endothal (exo,exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid) to mice (ip LD50 = 14 mg/kg) is attributed to the inhibition of protein phosphatase 2A (PP2A) at the cantharidin binding site. The potency is reduced by the introduction of a 2,3- or 5,6-double bond. Surprisingly, high toxicity (ip LD50's = 15-50 mg/kg) is restored in oxabicyclohepta-2(3),5(6)-dienes substituted in the 2- and 3-positions with bis(methyl carboxylate), bis(ethyl carboxylate), and diethyl phosphonate/ethyl carboxylate, whereas the dicarboxylic acid, bis(tert-butyl carboxylate), and bis(dimethyl phosphonate) are inactive. The diene adducts do not inhibit the cantharidin binding site of PP2A. Two observations provided an alternative working hypothesis that the active but not the inactive diene adducts are protoxicants: GC analyses revealed that selected bicyclic dienes readily undergo thermal dissociation by retro-Diels-Alder reactions to liberate disubstituted acetylenes; the liberated acetylenes have mouse ip LD50's of 8-25 mg/kg. Apparent exceptions to this hypothesis are that bicyclic dienes with bis(tert-butyl carboxylate) and bis(dimethyl phosphonate) substituents are not toxic, yet their corresponding acetylenes are quite toxic. These apparent anomalies are resolved by finding that only the toxic bicyclic dienes readily react with albumin and 4-nitrobenzenethiol and that their low-toxicity analogs are much less reactive. Albumin can be replaced by hemoglobin but not by myoglobin or chymotrypsin in reaction with a bicyclic diene indicating the importance of the free thiol group. Diethyl oxabicycloheptadienedicarboxylate readily reacts with GSH to give two products, which are also formed from the corresponding acetylene, identified as the cis and trans isomers of the GSH-acetylene conjugate. This is the first proposal, to our knowledge, that a retro-Diels-Alder-type reaction is involved in the metabolic activation of a toxicant.
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PMID:Retro-Diels-Alder reaction: possible involvement in the metabolic activation of 7-oxabicyclo[2.2.1]hepta-2(3),5(6)-diene-2,3-dicarboxylates and a phosphonate analog. 892 98

Erythropoietin (Epo) is the principal regulator of the production of circulating erythrocytes by controlling the proliferation, the differentiation and the survival of the erythroid progenitor cells. Early down-regulation of c-myb expression in erythroleukemia cells is a common feature of the action of Epo and chemical inducers of differentiation such as DMSO. Previously we have shown that in our Epo-responsive murine erythroleukemia cell line ELM-I-1, [Ca2+]i increasing agents can mimic the effect of Epo on c-myb expression and activate nuclear signal transduction processes involved in the induction of hemoglobin synthesis. These results also indicated that the Ca2+-induced down-regulation of c-myb expression and hemoglobin synthesis are mediated by the Ca2+/calmodulin dependent serine/threonine-specific protein phosphatase PP2B, calcineurin, but the Epo induced processes are not mediated by PP2B. In spite of this, we demonstrated in this paper that in ELM-I-1 cells the Epo-induced down-regulation of c-myb expression and hemoglobin production can be effectively enhanced by the simultaneously added [Ca2+]i-increasing agent, cyclopiazonic acid (CPA). This observation further supports the existence of at least two independent signalling pathways in the mechanism of Epo and [Ca2+]i increasing agents and the strong correlation between c-myb expression and hemoglobin production in differentiating cells. Although the c-AMP-response element binding protein (CREB) could be the common target of both calcium-dependent and -independent dephosphorylation, our results do not support the involvement of CREB in the regulation of c-myb gene expression. In addition to the calcineurin mediated down-regulation of c-myb expression, we have found a negative regulatory effect in the Ca2+-mediated transcriptional activation of certain genes. In response to [Ca2+]i-increasing agents in ELM-I-1 cells, both, egr-1 and c-fos mRNA expression increased significantly after the inhibition of calcineurin by cyclosporine A. Cyclosporin A exerted stimulatory effects on the egr-1 and c-fos expression also at lower (150-400 nM) intracellular Ca2+ levels. This potential co-regulation of c-myb, egr-1 and c-fos expression by calcineurin suggests that the negative modulation of egr-1 and c-fos expression may also be important for the induction of erythroid differentiation by [Ca2+]i-increasing agents. This negative modulation may also contribute to the Epo-induced differentiation in the case of a moderate increase of [Ca2+]i.
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PMID:Signalling mechanisms and the role of calcineurin in erythropoiesis. 1039 75

To investigate the efficacy and mechanism of action of vanadium salts as oral hypoglycemic agents, 16 type 2 diabetic patients were studied before and after 6 weeks of vanadyl sulfate (VOSO4) treatment at three doses. Glucose metabolism during a euglycemic insulin clamp did not increase at 75 mg/d, but improved in 3 of 5 subjects receiving 150 mg VOSO4 and 4 of 8 subjects receiving 300 mg VOSO4. Basal hepatic glucose production (HGP) and suppression of HGP by insulin were unchanged at all doses. Fasting glucose and hemoglobin A1c (HbA1c) decreased significantly in the 150- and 300-mg VOSO4 groups. At the highest dose, total cholesterol decreased, associated with a decrease in high-density lipoprotein (HDL). There was no change in systolic, diastolic, or mean arterial blood pressure on 24-hour ambulatory monitors at any dose. There was no apparent correlation between the clinical response and peak serum level of vanadium. The 150- and 300-mg vanadyl doses caused some gastrointestinal intolerance but did not increase tissue oxidative stress as assessed by thiobarbituric acid-reactive substances (TBARS). In muscle obtained during clamp studies prior to vanadium therapy, insulin stimulated the tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1), and Shc proteins by 2- to 3-fold, while phosphatidylinositol 3-kinase (PI 3-kinase) activity associated with IRS-1 increased 4.7-fold during insulin stimulation (P = .02). Following vanadium, there was a consistent trend for increased basal levels of insulin receptor, Shc, and IRS-1 protein tyrosine phosphorylation and IRS-1-associated PI 3-kinase, but no further increase with insulin. There was no discernible correlation between tyrosine phosphorylation patterns and glucose disposal responses to vanadyl. While glycogen synthase fractional activity increased 1.5-fold following insulin infusion, there was no change in basal or insulin-stimulated activity after vanadyl. There was no increase in the protein phosphatase activity of muscle homogenates to exogenous substrate after vanadyl. Vanadyl sulfate appears safe at these doses for 6 weeks, but at the tolerated doses, it does not dramatically improve insulin sensitivity or glycemic control. Vanadyl modifies proteins in human skeletal muscle involved in early insulin signaling, including basal insulin receptor and substrate tyrosine phosphorylation and activation of PI 3-kinase, and is not additive or synergistic with insulin at these steps. Vanadyl sulfate does not modify the action of insulin to stimulate glycogen synthesis. Since glucose utilization is improved in some patients, vanadyl must also act at other steps of insulin action.
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PMID:Metabolic effects of vanadyl sulfate in humans with non-insulin-dependent diabetes mellitus: in vivo and in vitro studies. 1072 21

Mg is an important determinant of erythrocyte cation transport system(s) activity. We investigated cation transport in erythrocytes from mice bred for high (MGH) and low (MGL) Mg levels in erythrocytes and plasma. We found that K-Cl cotransport activity was higher in MGL than in MGH erythrocytes, and this could explain their higher mean corpuscular hemoglobin concentration, median density, and reduced cell K content. Although mouse KCC1 protein abundance was comparable in MGL and MGH erythrocytes, activities of Src family tyrosine kinases were higher in MGH than in MGL erythrocytes. In contrast, protein phosphatase (PP) isoform 1 alpha (PP1 alpha) enzymatic activity, which has been suggested to play a positive regulatory role in K-Cl cotransport, was lower in MGH than in MGL erythrocytes. Additionally, we found that the Src family kinase c-Fgr tyrosine phosphorylates PP1 alpha in vitro. These findings suggest that in vivo downregulation of K-Cl cotransport activity by Mg is mediated by enhanced Src family kinase activity, leading to inhibition of the K-Cl cotransport stimulator PP1.
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PMID:K-Cl cotransport modulation by intracellular Mg in erythrocytes from mice bred for low and high Mg levels. 1154 77

Electrospray tandem mass spectrometry (ESI-MS/MS) was combined with biomolecular interaction analysis (BIA) to develop a method of direct protein identification after real-time analysis of protein protein interactions. Using this method, called BIA-MS/MS, we detected multiple p53-interacting proteins in whole tissue extracts from human placenta and liver. Peptide sequencing revealed three proteins whose interaction with p53 had not been previously reported: a cyclin-dependent kinase inhibitor p57/Kip2, a serine/threonine protein phosphatase PP1C, and hemoglobin. Using our system, unambiguous sequence information can be obtained at the femto- to picomole level after repeating the recovery procedure five times. Furthermore, the association and dissociation constants are easily determined by kinetic analysis. This system provides a powerful tool for analyzing complex biological materials in a simple but highly specific and sensitive manner.
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PMID:Identification of novel p53-binding proteins by biomolecular interaction analysis combined with tandem mass spectrometry. 1266 91

Diabetes mellitus, a frequent metabolic complication in liver transplant recipients, may be produced by the diabetogenic effect of calcineurin inhibitors cyclosporine and tacrolimus. The aim of this study was to investigate the safety and metabolic effects of a gradual switch from cyclosporine or tacrolimus to mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient was withdrawn from the study due to gastrointestinal side effects. Of the 11 remaining patients, cyclosporine or tacrolimus was completely withdrawn in five patients. Two patients developed suspected acute rejection episodes that were controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and C-peptide levels were significantly lower at 3 and 6 months after the initiation of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid levels were significantly reduced after the change of treatment. In conclusion, a switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce beneficial metabolic effects in diabetic liver transplant recipients, but poses a risk of graft rejection.
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PMID:Conversion from calcineurin inhibitors to mycophenolate mofetil in liver transplant recipients with diabetes mellitus. 1296 32

The incidence of diabetes in kidney transplant recipients is between 4 and 20% in patients previously not affected by this pathology. This difference is partially due to the immunosuppressive therapy administered. The incidence of diabetes is very high during the first quarter after the transplant, and it becomes stable during the following quarters. The presence of diabetes - evaluated by postprandial glycemia and glycated hemoglobin - should be checked quarterly during the first year after the transplant, every six months during the second year, and yearly starting from the third year. The immunosuppressive therapy (calcineurin inhibitors and steroids), familial history, age, race, and weight (BMI) are among the risk factors of diabetes post-transplant. An increased risk of rejection seems to be among the principal consequences of diabetes in transplant recipients. Moreover, these patients are more prone to infections, cardiovascular disease, and the degenerative complications of diabetes. These facts increase the risk of organ insufficiency, morbidity, and mortality. To manage diabetes in transplant recipients it is necessary to identify at-risk patients before the transplantation, thus avoiding complicated and hazardous examinations after the transplant. After the transplantation, the modifiable risk factors, such as the immunosuppressant drugs used and the control of body weight, must be checked. The control of hypertension is important as well.
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PMID:[The incidence, clinical implications, and risk factors of diabetes mellitus]. 1452 6


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