Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of the soluble fraction derived from Mycoplasma gallisepticum cells with [gamma-32P]ATP results in the phosphorylation of several endogenous proteins. One protein with an apparent molecular mass of 55 kDa was the acceptor of more than 95% of the radioactive phosphate. This protein was also found to be radiolabeled in intact cells grown in the presence of [32P]orthophosphate. Acid hydrolysis of the phosphorylated 55-kDa protein followed by two-dimensional electrophoresis revealed that the 32P-labeled material co-migrated with phosphoserine. The in vitro phosphorylation of the 55-kDa protein has an optimum pH of 5.5-6.0 and is not affected by various metabolites of glycolysis, by cAMP or by calmodulin with or without Ca2+. The phosphorylation is dependent upon divalent cations, a dependency that is best fulfilled by the simultaneous addition of Ca2+ and Zn2+ that act in a specific and cooperative manner. Of a variety of possible exogenous protein acceptors tested, the endogenous protein kinase was capable to phosphorylate only phosvitin. The phosphorylation of the 55-kDa protein is reversible through the activity of a phosphoprotein phosphatase present in the soluble fraction of M. gallisepticum. The phosphoprotein phosphatase has an optimum pH of 7.5-8.0, is inhibited by NaF and stimulated to a large extent by inorganic phosphate and arsenate and to a lesser extent by pyrophosphate ATP and ADP. The possible association of the reversible protein phosphorylation to cell shape and gliding motility of M. gallisepticum are discussed.
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PMID:Protein phosphorylation in Mycoplasma gallisepticum. 284 67

Inspection of the genomes for the bacteria Bacillus subtilis 168, Borrelia burgdorferi B31, Escherichia coli K-12, Haemophilus influenzae KW20, Helicobacter pylori 26695, Mycoplasma genitalium G-37, and Synechocystis sp PCC 6803 and for the archaeons Archaeoglobus fulgidus VC-16 DSM4304, Methanobacterium thermoautotrophicum delta H, and Methanococcus jannaschii DSM2661 revealed that each contains at least one ORF whose predicted product displays sequence features characteristic of eukaryote-like protein-serine/threonine/tyrosine kinases and protein-serine/threonine/tyrosine phosphatases. Orthologs for all four major protein phosphatase families (PPP, PPM, conventional PTP, and low molecular weight PTP) were present in the bacteria surveyed, but not all strains contained all types. The three archaeons surveyed lacked recognizable homologs of the PPM family of eukaryotic protein-serine/threonine phosphatases; and only two prokaryotes were found to contain ORFs for potential phosphatases from all four major families. Intriguingly, our searches revealed a potential ancestral link between the catalytic subunits of microbial arsenate reductases and the protein-tyrosine phosphatases; they share similar ligands (arsenate versus phosphate) and features of their catalytic mechanism (formation of arseno-versus phospho-cysteinyl intermediates). It appears that all prokaryotic organisms, at one time, contained the genetic information necessary to construct protein phosphorylation-dephosphorylation networks that target serine, threonine, and/or tyrosine residues on proteins. However, the potential for functional redundancy among the four protein phosphatase families has led many prokaryotic organisms to discard one, two, or three of the four.
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PMID:The serine, threonine, and/or tyrosine-specific protein kinases and protein phosphatases of prokaryotic organisms: a family portrait. 986 22

Mycoplasma pneumoniae belongs to the mollicutes, a group of bacteria that have strongly reduced genomes but that are nevertheless capable of independent life. With only three transcription factors, the regulatory features of these bacteria are very limited. Thus, posttranslational regulation might be important for M. pneumoniae. In addition to the highly specific HPr kinase, the M. pneumoniae prkC gene encodes the serine/threonine protein kinase C. In order to study the function(s) of this kinase, we isolated an M. pneumoniae mutant affected in PrkC. This mutation resulted in nonadherent growth and loss of cytotoxicity. Examination of the phosphorylation profile of the prkC mutant suggested that phosphorylation of cytadherence proteins was affected by the loss of this kinase. In contrast, inactivation of the prpC gene affecting the protein phosphatase that antagonizes PrkC-dependent phosphorylation resulted in more intensive phosphorylation of the cytadherence proteins HMW1 and HMW3 of the major adhesin P1 and of the surface protein MPN474. Moreover, loss of PrkC affects not only the phosphorylation state of the cytadherence proteins but also their intracellular accumulation. However, the expression of the corresponding genes was not affected by PrkC, suggesting that PrkC-dependent phosphorylation results in stabilization of the cytadherence proteins. The HMW proteins and P1 are part of the so-called terminal organelle of M. pneumoniae that is involved in gliding motility, cell division, and adhesion to host epithelial tissues. Our observations suggest that the posttranslational modification of cytadherence proteins by PrkC is essential for the development and function of the M. pneumoniae terminal organelle.
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PMID:The stability of cytadherence proteins in Mycoplasma pneumoniae requires activity of the protein kinase PrkC. 1985 94

Mycoplasma pneumoniae belongs to the Mollicutes, the group of organisms with the smallest genomes that are capable of host-independent life. These bacteria show little regulation in gene expression, suggesting an important role for the control of protein activities. We have studied protein phosphorylation in M. pneumoniae to identify phosphorylated proteins. Two-dimensional gel electrophoresis and mass spectrometry allowed the detection of 63 phosphorylated proteins, many of them enzymes of central carbon metabolism and proteins related to host cell adhesion. We identified 16 phosphorylation sites, among them 8 serine and 8 threonine residues, respectively. A phosphoproteome analysis with mutants affected in the two annotated protein kinase genes or in the single known protein phosphatase gene suggested that only one protein (HPr) is phosphorylated by the HPr kinase, HPrK, whereas four adhesion-related or surface proteins were targets of the protein kinase C, PrkC. A comparison with the phosphoproteomes of other bacteria revealed that protein phosphorylation is evolutionarily only poorly conserved. Only one single protein with an identified phosphorylation site, a phosphosugar mutase (ManB in M. pneumoniae), is phosphorylated on a conserved serine residue in all studied organisms from archaea and bacteria to man. We demonstrate that this protein undergoes autophosphorylation. This explains the strong conservation of this phosphorylation event. For most other proteins, even if they are phosphorylated in different species, the actual phosphorylation sites are different. This suggests that protein phosphorylation is a form of adaptation of the bacteria to the specific needs of their particular ecological niche.
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PMID:The phosphoproteome of the minimal bacterium Mycoplasma pneumoniae: analysis of the complete known Ser/Thr kinome suggests the existence of novel kinases. 2009 88

Protein post-translational modifications (PTMs) represent important regulatory states that when combined have been hypothesized to act as molecular codes and to generate a functional diversity beyond genome and transcriptome. We systematically investigate the interplay of protein phosphorylation with other post-transcriptional regulatory mechanisms in the genome-reduced bacterium Mycoplasma pneumoniae. Systematic perturbations by deletion of its only two protein kinases and its unique protein phosphatase identified not only the protein-specific effect on the phosphorylation network, but also a modulation of proteome abundance and lysine acetylation patterns, mostly in the absence of transcriptional changes. Reciprocally, deletion of the two putative N-acetyltransferases affects protein phosphorylation, confirming cross-talk between the two PTMs. The measured M. pneumoniae phosphoproteome and lysine acetylome revealed that both PTMs are very common, that (as in Eukaryotes) they often co-occur within the same protein and that they are frequently observed at interaction interfaces and in multifunctional proteins. The results imply previously unreported hidden layers of post-transcriptional regulation intertwining phosphorylation with lysine acetylation and other mechanisms that define the functional state of a cell.
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PMID:Cross-talk between phosphorylation and lysine acetylation in a genome-reduced bacterium. 2237 19

We report three pediatric heart transplant (HTx) patients whose respiratory symptoms were successfully controlled with long-term, low-dose macrolide administration (clarithromycin: CAM; approximately 2.5 mg/kg bid). The first case was an 18-year-old boy who underwent HTx at the age of three for dilated cardiomyopathy (DCM). Beginning at age 5, he had repeated fevers and respiratory symptoms. He was diagnosed with chronic sinusitis at age 11 and sinobronchial syndrome with mild bronchiectasis at age 14. Administration of long-term, low-dose CAM and otolaryngeal topical therapy led to significant improvement of his symptoms. The second case was a 7-year-old boy who underwent HTx for DCM at age one. Starting at age 4, he had repeated fevers and cough due to atelectasis and pneumonia. As antibiotics and respiratory physical therapy proved ineffective, he received long-term, low-dose CAM, resulting in successful control of his atelectasis and recurrent pneumonia. The third case was a 13-year-old boy who underwent HTx at age 6 for DCM. He had chronic sinusitis starting at age 7, and was diagnosed with obstructive sleep apnea syndrome at age 10. Adenotonsillectomy and continuous positive airway pressure support therapy were indicated. At age 13, long-term, lowdose CAM administration was started following mycoplasma infection. In all three cases, the levels of calcineurin inhibitors (cyclosporine and tacrolimus) and everolimus were kept in the optimal range with careful drug monitoring. Longterm, low-dose macrolide administration effectively prevents and treats respiratory complications in pediatric HTx patients as long as attention is paid to potential drug interactions.
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PMID:The successful management of respiratory complications with long-term, low-dose macrolide administration in pediatric heart transplant recipients. 2529 1

Serine/threonine protein phosphatases have been described in many pathogenic bacteria as essential enzymes involved in phosphorylation-dependent signal transduction pathways and frequently associated with the virulence of these organisms. An inspection of Mycoplasma synoviae genome revealed the presence of a gene (prpC) encoding a putative protein phosphatase of the protein phosphatase 2C (PP2C) subfamily. Here, we report a complete biochemical characterization of M. synoviae phosphatase (PrpC) and the particular role of metal ions in the structure-function relationship of this enzyme. PrpC amino acid sequence analysis revealed that all the residues involved in the dinuclear metal center and the putative third metal ion-coordinating residues, conserved in PP2C phosphatases, are present in PrpC. PrpC is a monomeric protein able to dephosphorylate phospho-substrates with Mn(2+) ions' dependence. Thermal stability analysis demonstrated the enzyme stability at mild temperatures and the influence of Mn(2+) ions in this property. Mass spectrometry analysis suggested that three metal ions bind to PrpC, two of which with an apparent high-affinity constant. Mutational analysis of the putative third metal-coordinating residues, Asp122 and Arg164, revealed that these variants exhibited a weaker binding of manganese ions, and that both mutations affected PrpC phosphatase activity. According to these results, PrpC is a metal-dependent protein phosphatase member with an improved stability in the holo form and with Asp122, possibly implicated in the third metal-binding site, essential to catalytic activity.
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PMID:The unique serine/threonine phosphatase from the minimal bacterium Mycoplasma synoviae: biochemical characterization and metal dependence. 2537 51

While a good number of studies have demonstrated that modern, man-made ambient electromagnetic fields can have both stimulatory and inhibitory effect on immune system function, the precise mechanisms have yet to be completely elucidated. It is hypothesized here that, depending on the parameters, one of the means by which long-term electromagnetic field exposure has the potential to eventually lead to immunosuppression is via downstream inhibition of the enzyme calcineurin - a protein phosphatase, which activates the T-cells of the immune system and can be blocked by pharmaceutical agents. Calcineurin is the target of a class of pharmaceuticals called calcineurin inhibitors (e.g., cyclosporine, pimecrolimus and tacrolimus). When organ transplant recipients take such pharmaceuticals to prevent or suppress organ transplant rejection, one of the major side effects is immunosuppression leading to increased risk of opportunistic infection: e.g., fungal, viral (Epstein-Barr virus, cytomegalovirus), atypical bacterial (Nocardia, Listeria, mycobacterial, mycoplasma), and parasitic (e.g., toxoplasmosis) infections. Frequent anecdotal reports, as well as a number of scientific studies, have shown that electromagnetic field exposures may indeed produce the same effect: a weakened immune system leading to an increase in the same or similar opportunistic infections: i.e., fungal, viral, atypical bacterial, and parasitic infections. Furthermore, numerous research studies have shown that man-made electromagnetic fields have the potential to open voltage-gated calcium channels, which can in turn produce a pathological increase of intracellular calcium, leading downstream to the pathological production of a series of reactive oxygen species. Finally, there are a number of research studies demonstrating the inhibition of calcineurin by a pathological production of reactive oxygen species. Hence, it is hypothesized here that exposures to electromagnetic fields have the potential to inhibit immune system response by means of an eventual pathological increase in the influx of calcium into the cytoplasm of the cell, which induces a pathological production of reactive oxygen species, which in turn can have an inhibitory effect on calcineurin. Calcineurin inhibition leads to immunosuppression, which in turn leads to a weakened immune system and an increase in opportunistic infection.
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PMID:Electromagnetic fields may act via calcineurin inhibition to suppress immunity, thereby increasing risk for opportunistic infection: Conceivable mechanisms of action. 2881 75