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

---

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

The immunosuppressive peptide cyclosporin A inhibits the growth of malaria parasites in vitro and in vivo, but little is known about its mechanism of antimalarial action. The immunosuppressive action of cyclosporin A is believed to result from binding of the drug to cyclophilins (intracellular peptidyl-prolyl cis-trans isomerases), and inhibition of the protein phosphatase calcineurin by the cyclosporin A-cyclophilin complex. Two immunosuppressive macrolides, FK506 and rapamycin, bind to a distinct isomerase, FKBP12, and the FK506-FKBP complex also inhibits calcineurin. Calcineurin itself is apparently involved in signal transduction between the T-cell membrane and nucleus, and its inhibition blocks T-cell activation. Rapamycin inhibits a later step in T-cell proliferation. Peptidyl-propyl cis-trans isomerase activity was detected in extracts of Plasmodium falciparum. It was completely inhibited by concentrations of cyclosporin A above 0.1 microM, but not by FK506 or rapamycin, and probably represented one or more cyclophilins. Comparison of the antimalarial and anti-isomerase activities of a series of cyclosporin analogues failed to reveal a correlation between the two properties. Cyclosporin A and its more active 8'-oxymethyl-dihydro-derivative, in combination with the cyclophilin-containing P. falciparum extract, inhibited the protein phosphatase activity of bovine calcineurin. Therefore inhibition of a putative P. falciparum calcineurin by a complex of CsA and cyclophilin might be responsible for the antimalarial action of the drug. The most active cyclosporin, however, was a 3'-keto-derivative of cyclosporin D (SDZ PSC-833) which inhibited P. falciparum growth with a 50% inhibitory concentration (IC50) of 0.032 microM (compared with 0.30 microM for cyclosporin A), but was a poor inhibitor of the parasite isomerase. 3'-Keto-cyclosporin D has negligible immunosuppressive activity, but it strongly inhibits the P-glycoprotein of multi-drug resistant mammalian tumour cells. FK506 and rapamycin were also active antimalarials (IC50 of 1.9 and 2.6 microM, respectively) but in the absence of detectable FKBP in P. falciparum extracts, their mechanisms of antimalarial action remain unclear.
...
PMID:Roles of peptidyl-prolyl cis-trans isomerase and calcineurin in the mechanisms of antimalarial action of cyclosporin A, FK506, and rapamycin. 752 Jun 96

The nontransformed steroid receptors contain several non-steroid binding proteins, such as hsp90, hsp70, and p59. Recently, we and others have shown that p59 (FKBP59) is an immunophilin which binds two potent immunosuppressants, FK506 and rapamycin. This raises the possibility that FK506 or rapamycin may modify the function of steroid receptors. To develop this line of inquiry, we chose a yeast model system in which the human progesterone receptor form B (hPR-B) was cotransformed with a reporter gene. The reporter contains two copies of a progesterone response element/glucocorticoid response element (PRE/GRE) upstream of the CYC1 promoter which are linked to the lacZ gene of Escherichia coli. We found that FK506 potentiated the ability of progesterone in activating transcription. To gain insight into the mechanism of FK506's regulation of PR action, we questioned whether calcineurin is involved, because it has been shown that FK506 is a specific inhibitor of calcineurin, a Ca(2+)- and calmodulin-regulated phosphatase, through the formation of an FKBP12-FK506-calcineurin-calmodulin complex. We found that 15-O-desmethyl-FK520, an FK506 analogue which is an excellent ligand of FKBP12, but a poor inhibitor of calcineurin, failed to induce the same effect as FK506. We also found that calmidazolium, a calmodulin antagonist, mimicked FK506's action. Furthermore, immunoblot analysis showed that both FK506 and calmidazolium potentiated the effect of progesterone in decreasing the mobility of hPR-B upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This suggests that FK506 and calmidazolium may cooperate with progesterone in increasing the level of hPR-B phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Potentiation of progesterone receptor-mediated transcription by the immunosuppressant FK506. 752 Dec 10

Antigen-specific signal transduction leading to IL2 induction and secretion in the T cell line 171 is augmented by association of p56lck with CD4. Although no change in cytoplasmic calcium level ([Ca2+]i) was detectable during antigen-specific signal transduction of 171-CD4+ cells, IL2 induction was inhibited by FK506 and CsA. Since these drugs are thought to act selectively by inhibiting calcineurin, a calcium-calmodulin-dependent protein phosphatase associated with activation of the IL2 promoter, we considered the possibility that calcineurin is constitutively active in 171 cells. However, we found no evidence for this because PMA failed to supplement any putatively active calcineurin to induce IL2 secretion. We suggest that IL2 secretion induced by antigen presentation to TCR/CD4/p56lck requires an FK506 and cyclosporin A-sensitive step which may be independent of calcium signaling. Rapamycin did not inhibit IL2 secretion induced by TCR/CD4/p56lck, emphasizing the specific action of FK506 and cyclosporin A.
...
PMID:FK506 and cyclosporin A each inhibit antigen-specific signaling in the T cell line 171 in the absence of a calcium signal. 752 30

The immunosuppressive action of the drug FK506 involves inhibition of calcineurin in T-lymphocytes by a complex of FK506 and an FK506 binding protein, FKBP12, a member of the immunophilin protein family. The functional role of brain immunophilins is, however, unclear. We show here that FK506 is a powerful neuroprotective agent in an in vivo model of focal cerebral ischaemia when administered up to 60 min post-occlusion. The minimum effective neuroprotective dose is comparable with the immunosuppressant dose in humans, suggesting that FK506 may have clinical potential for the treatment of stroke. Although the related immunosuppressants rapamycin and cyclosporin failed to reduce brain damage, the finding that rapamycin pretreatment blocked the effect of FK506 confirms a role for immunophilins in the neuroprotective mechanism.
...
PMID:Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. 752 3

The effect of recombinant FKBP-59/HBI or of its first N-terminal domain FKBP-59/HBI-I on the phosphatase activity of calcineurin (a Ca(+2)-calmodulin dependent phosphatase) was tested in vitro in the presence or absence of the immunosuppressant drug FK506. Contrarily to the inhibition observed with the immunosuppressant complex FKBP-12-FK506, no significant inhibition was observed with FKBP-59/HBI or FKBP-59/HBI-I in the presence of FK506, even though FKBP-59/HBI-1 is nearly 55% homologous to the immunophilin FKBP-12. Inhibition was tested both with native calcineurin (calcineurin A: Mr 58-59 kDa) and with protease activated, calmodulin independent calcineurin (calcineurin A: Mr 45 kDa). There was no competitive effect of FKBP-59 on the inhibitory activity of the FKBP-12-FK506 complex, even when the molar concentration of FKBP-59/HBI was 100 times higher than that of FKBP-12. Clearly, although the first domain of FKBP-59/HBI displays several structural and functional features of FKBP-12, it does not interact with calcineurin.
...
PMID:Rabbit FKBP-59/HBI does not inhibit calcineurin activity in vitro. 752 47

Calcineurin (CaN) immunoreactivity and content increased markedly in kindled rat brain, and this increment was due to CaN in the membrane fraction. Investigation of the effects of cyclosporin A and FK506 (immunosuppressants which inhibit CaN activity in T lymphocytes) in the kindling phenomena showed that the kindling stage progression was reversibly blocked by these drugs. These findings suggest that calcineurin may play an essential role in acquiring epileptogenesis in kindling.
...
PMID:Immunosuppressants and calcineurin inhibitors, cyclosporin A and FK506, reversibly inhibit epileptogenesis in amygdaloid kindled rat. 752 29

The calcium/calmodulin-regulated phosphatase calcineurin (CN) is the site of action of the immunosuppressive drugs cyclosporin A (CsA) and FK506. CN has recently been established as a key signaling enzyme in the T cell signal transduction cascade and an important regulator of transcription factors such as NF-AT and OAP/Oct-1, which are involved in the expression of a number of important T cell early genes. CsA and FK506 act by forming complexes with their respective intracellular receptors cyclophilin and FKBP (immunophilins), which can then bind to CN, inhibiting its enzymatic activity and thereby preventing early gene expression. CN is comprised of two subunits: a 59-kDa catalytic subunit (CNA), which contains a calmodulin binding domain and autoinhibitory region, and a 19-kDa intrinsic calcium binding regulatory subunit (CNB). In this study, we have utilized a series of deletion mutants of the CNA subunit to investigate the subunit and molecular requirements that govern the interaction of CN with drug-immunophilin complexes. The calmodulin binding and autoinhibitory domains of the CNA subunit were found to be dispensable for the binding of CN to drug-immunophilin complexes. In contrast, we found that the regulatory CNB subunit appears to play an obligatory role in this interaction and have defined an amino acid sequence of the CNA subunit which forms the binding site for CNB. Although necessary, the CNB subunit per se is not sufficient to mediate an interaction with drug-immunophilin complexes; amino acid residues of the CNA subunit, specifically a region located within the putative catalytic domain, are also required for the interaction of CN with both FKBP-FK506 and cyclophilin A-CsA.
...
PMID:Molecular analysis of the interaction of calcineurin with drug-immunophilin complexes. 752 7

The binding of the FK506/FKBP-12 complex to calcineurin (CN), its putative target for immunosuppression, involves recognition of solvent-exposed regions of the ligand as well as FKBP-12 residues near the active site. The R42K, H87V double mutation of FKBP-12 decreases the CN affinity of the complex by 550-fold [Aldape, R. A., Futer, O., DeCenzo, M. T., Jarrett, B. P., Murcko, M. A., & Livingston, D. J. (1992) J. Biol. Chem. 267, 16029-16032]. This work reports the solution structure of 13C-labeled FK506 bound to R42K, H87V FKBP-12. Assignments and NOE measurements at three mixing times were made from inverse-detected 1H-13C NMR experiments. Structures were calculated by several different methods, including distance geometry, restrained molecular dynamics, and molecular dynamics with time-averaged restraints. The NMR structures of the ligand are very well defined by the NOE restraints and differ slightly from the X-ray structure in regions that are involved in crystal packing. Comparison with the NMR structure of FK506 bound to wild-type FKBP-12 reveals that the R42K, H87V mutation causes the ligand backbone near C16 to move by 2.5 to 4.5 A, reorients 15-MeO by 90 degrees, and shifts 13-MeO by approximately 1.5 A. FK506 appears to undergo a concerted, mutationally induced shift in the binding pocket, with the greatest changes occurring in the effector region of the drug. The altered effector conformation of mutant-bound FK506 may perturb interactions between the drug and CN, thus accounting for the effect of the double mutation upon the CN inhibitory activity of the complex.
...
PMID:Solution structure of FK506 bound to the R42K, H87V double mutant of FKBP-12. 752 62

The immunosuppressants cyclosporin A and FK506, when complexed with their intracellular receptors, prevent T cell activation by directly binding to the phosphatase calcineurin. We have used molecular modeling and mutagenesis to identify sites on calcineurin important for this interaction. We have created calcineurins that are resistant to both cyclosporin A and FK506 by mutating specific residues in CnB, a calcium-binding protein that regulates the catalytic subunit, CnA. Significantly, on a model of CnB, these mutations map to the latch region, an element of tertiary structure that forms when CnB binds CnA. In addition, we show that this latch region plays an important role in activating the catalytic subunit CnA. These results suggest a molecular mechanism for suppression of calcineurin by cyclosporin A and FK506 involving their binding to the same region of CnB used for allosterically activating CnA.
...
PMID:The latch region of calcineurin B is involved in both immunosuppressant-immunophilin complex docking and phosphatase activation. 752 78

The microbial products FK506 and CsA are potent immunosuppressive agents that prevent early transcriptional events in TcR-mediated activation. Their mode of action is dependent upon the inhibition of calcineurin, a serine/threonine phosphatase positioned within the calcium-dependent signaling pathway. TcR-mediated activation of thymocytes constitutes an important prerequisite for their development and selection to mature T cells. Disruption of the cross-talk between thymic APC and thymocytes results in the loss of normal T cell ontogeny. To study the role of calcineurin in T cell maturation and repertoire selection in vivo, mice were treated with either FK506 or CsA. Administration of either drug inhibited the progression of CD4+CD8+ positive thymocytes to mature single positive T cells. Furthermore, both drugs disrupted the process of negative thymic selection, causing an increased frequency of self-reactive cells among the few positively selected T cells. These effects correlated directly with the degree of inhibition of in vivo calcineurin enzyme activity. Blocking calcineurin activity appears to disrupt positive thymic selection and to prevent the deletion of self-reactive thymocytes.
...
PMID:Disruption of T cell development and repertoire selection by calcineurin inhibition in vivo. 752 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---