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)

FK-506 inhibits Ca(2+)-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with related biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis-trans peptidyl-prolyl isomerase activity (PPIase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufficient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used L-685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although L-685,818 bound with high affinity to FKBP-12 and inhibited its PPIase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, L-685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPIase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.
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PMID:The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin. 138 Sep 76

FK-506 blocks T cell activation by preventing lymphokine gene transcription through formation of a complex with FKBP12 that inhibits calcineurin phosphatase activity. Immunosuppressive FK-506 analogs (agonists) have been generated whose potency correlates with calcineurin inhibition. Nonimmunosuppressive antagonist analogs have also been identified, including L-685,818, which binds to FKBP12 but does not inhibit calcineurin. We describe a novel property of FK-506 analog, characterized as a mixed agonist/antagonist immunosuppressive activity. It is displayed by L-688,617, the 32 O-methoxyethoxymethyl derivative of the agonist L-683,590 (C21-ethyl). Although it binds to FKBP12 similarly to L-683,590, L-688,617 incompletely suppressed T cell proliferation induced by optimal activation and enhanced that induced by supraoptimal activation. In the latter situation, L-688,617 suppressed IL-2 production only partially but blocked activation-driven cell death. Moreover, a 1000-fold molar excess of L-688,617 antagonized the immunosuppressive activity of L-683,590. L-688,617 inhibited calcineurin phosphatase activity in cells only partially. The unique agonist/antagonist activity of L-688,617 may therefore reflect its high affinity for FKBP12, combined with a reduced ability of the drug-FKBP12 complex to inhibit calcineurin function. However, in a cell-free system, L-688,617 completely blocked this function when a large excess of FKBP12 over calcineurin was present, suggesting that the intracellular concentration of FKBP12 may be a limiting factor that prevents full agonist activity of L-688,617 in cells.
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PMID:Mixed agonist/antagonist activity of an FK-506-related immunosuppressant: biological and biochemical characterization. 878 38

We show that the nonimmunosuppressive analogues of the immunosuppressive drugs FK506, rapamycin and cyclosporin A promote neurite outgrowth both in PC12 cells and sensory neuronal cultures of dorsal root ganglia with potencies resembling their immunosuppressive homologues. Neurotrophic potencies of the immunophilin ligands resemble their potencies in binding to and inhibiting the rotamase activity of FKBP-12 of cyclophilin. Since nonimmunosuppressive immunophilin ligands, which are devoid of calcineurin inhibitory activity, are equally neurotrophic, inhibition of calcineurin activity is not the mediator of the neurotrophic effects. The immunophilin ligands are neurotrophic in intact animals. FK506 and L-685,818 (the C18-hydroxy, C21-ethyl derivative of FK506) treatment of rats with crushed sciatic nerves enhances both functional and morphologic recovery. The striking potency of these agents, their bioavailability and the dissociation of neurotrophic from immunosuppressant actions argue for their therapeutic relevance in the treatment of neurodegenerative diseases.
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PMID:Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. 909 76

The nephrotoxic potential of ascomycin, the C21-ethyl analogue of FK506, was defined and ways explored to enhance its detection. After 14-day dosing in the Fischer-344 rat, FK506 and ascomycin reduced creatinine clearance by >50% at doses of 1 and 3 mg/kg, i.p., respectively. Ascomycin also had a 3-fold lower immunosuppressive potency in a popliteal lymph node hyperplasia assay, resulting in an equivalent therapeutic index consistent with a common mechanistic dependence on calcineurin inhibition. Renal impairment with different routes of administration was correlated with pharmacokinetics. Sensitivity of detection was not adequate with shorter dosing durations in rats with unilateral nephrectomy or in mice using a cytochrome P-450 inhibitor, SKF-525A. In 14-day studies, nephrotoxicity was not induced by continuous i.p. infusion of ascomycin at 10 mg/kg/day or daily oral administration (up to 50 mg/kg/day) in rats on a normal diet, nor by continuous i.v. infusion (up to 6 mg/kg/day) in rats on a low salt diet to enhance susceptibility. The lack of toxicity at high oral doses of FK506 or ascomycin, and the finding of non-linear oral pharmacokinetics of ascomycin show that this drug class has an oral absorption ceiling. The negative results with continuous infusion suggest that ascomycin nephrotoxicity is governed by peak drug levels. In addition to defining ways to meaningfully compare the nephrotoxic potential of FK506 derivatives, these results have implications for overall safety assessment and improved clinical use.
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PMID:Nephrotoxicity studies of the immunosuppressants tacrolimus (FK506) and ascomycin in rat models. 957 Mar 31

The effects of tautomycin and its derivatives on protein phosphatases PP1 and PP2A and their apoptosis-inducing activity toward human leukemia Jurkat cells were examined, and the relationship between chemical structure and function was discussed. Among the compounds we examined, tautomycin was the most potent inhibitor and the most effective inducer of apoptosis. It inhibited PP1 and PP2A enzymatic activity concentration-dependently with IC50 values of 20 and 75 pM, respectively, in the presence of 0.01% Brij-35, and an LC50 value of 1 microM. Esterification of the anhydride moiety of tautomycin markedly increased the IC50 for the protein phosphatases. The C1'-C7' fragment of tautomycin had no inhibitory effect, but the fragment containing the C22-C26 moiety was inhibitory. These results suggest that the C22-C26 moiety is essential for inhibition of protein phosphatase activity and that the anhydride moiety enhances the inhibition. However, the esterification of the anhydride did not decrease, nor did the inclusion of the C22-C26 moiety increase the apoptosis-inducing activity. On the other hand, the C1-C18 moiety of tautomycin was essential for induction of apoptosis, and the conformation and the arrangement of functionalities of the C18-C26 carbon chain affected the apoptosis activity. However, modification of C1-C18, C1-C21, or C1-C26 compounds had little effect on phosphatase inhibitory activity. Our results strongly suggest that different moieties of tautomycin are involved in protein phosphatase inhibition and induction of apoptosis.
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PMID:Different moieties of tautomycin involved in protein phosphatase inhibition and induction of apoptosis. 960 23

Three immunosuppressant drugs, cyclosporin A, FK506 and rapamycin were compared in their three-dimensional structures by computer modelling. The pairwise comparisons of cyclosporin A, FK506 and rapamycin show two structurally common fragments. One fragment is Mle9-Bmt1 region in cyclosporin A, C22-O5 region in FK506 and C29-O5 region in rapamycin. Another fragment is Mle4-Mle6 region in cyclosporin A and C14-C21 regions in FK506 and rapamycin. The correspondence of the structurally analogous regions with the regions which are involved in the interactions with peptidyl-prolyl cis/trans isomerases and calcineurin or FKBP-rapamycin-associated protein is discussed.
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PMID:Analogous conformations of both binding and effector regions in cyclosporin A, FK506 and rapamycin. 968 Jun 90

FK506 and rapamycin are immunosuppressants that inhibit signalling cascades required for T-cell activation, yet both are natural products of Streptomyces that live in the soil. FK506 and rapamycin also have potent antimicrobial activity against yeast and pathogenic fungi, suggesting a natural role in inhibiting growth of competing micro-organisms. The immunosuppressive and antimicrobial activities of FK506 and rapamycin are mediated by binding to the FKBP12 prolyl isomerase and the resulting FKBP12/FK506 and FKBP12/rapamycin complexes inhibit conserved protein targets, either the phosphatase calcineurin or the TOR (target of rapamycin) kinases, respectively. Streptomyces sp., 'Streptomyces hygroscopicus subsp. ascomyceticus' and Streptomyces hygroscopicus, which produce FK506, FK520 (also known as ascomycin, a C21 ethyl derivative of FK506) and rapamycin, respectively, produced toxins that inhibited the growth of competing cells of the yeast Saccharomyces cerevisiae and the pathogenic fungus Cryptococcus neoformans. Yeast and fungal mutants lacking FKBP12 or expressing dominant drug-resistant calcineurin or TOR mutants were resistant to FK506 and rapamycin, and to the toxins produced by Streptomyces. Streptomyces strains with mutations in the FK506 or rapamycin biosynthetic enzymes were impaired in toxin production. Finally, the toxins secreted by 'S. hygroscopicus subsp. ascomyceticus' and S. hygroscopicus promoted formation of FKBP12/calcineurin and FKBP12/TOR complexes in a two-hybrid assay and mutations that rendered calcineurin or TOR drug-resistant prevented interaction. These observations support the hypothesis that Streptomyces evolved to secrete FK506, FK520 and rapamycin as toxins to inhibit the growth of competing yeast and fungi.
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PMID:Secretion of FK506/FK520 and rapamycin by Streptomyces inhibits the growth of competing Saccharomyces cerevisiae and Cryptococcus neoformans. 1046 65

A convergent, asymmetric synthesis of the protein phosphatase inhibitor, tautomycin, is described. The natural product was constructed by joining two major fragments of comparable complexity at the C21-C22 bond. Absolute stereochemistry of the C1-C21 ketone originates from (S)-citronellene and (2R,3S)-geraniol epoxide. The anti stereochemical relationships at C6-C7 and C18-C19 were introduced with Duthaler's chiral titanium propionic enolate. Syn stereochemical relationships at C13-C14 and C23-C24 were established using an Evan's oxazolidinone chiral auxiliary. The spiroketal was efficiently constructed via a one-pot double-alkylation-spirocyclization sequence with acetone N,N-dimethylhydrazone serving as the central linchpin. Final coupling of the two halves using a chelation-controlled Mukaiyama aldol addition followed by deprotection yielded synthetic tautomycin that is identical to the natural product.
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PMID:Total Synthesis of the Serine/Threonine-Specific Protein Phosphatase Inhibitor Tautomycin(1). 1167 14

We have accomplished the synthesis of 13C-labeled tautomycin at the C18, C19, C21, and C22 positions starting from 100% [13C]triethylphosphonoacetate for the purpose of elucidating the dynamics and conformation of the C17-C26 moiety. NMR spectroscopy of 13C-labeled tautomycin revealed strong binding with protein phosphatase type 1 and new features in the 13C NMR spectrum, such as the very small three-bond coupling constants (2J).
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PMID:Synthesis of [18,19,21,22-(13)C4]-labeled tautomycin as an NMR probe of protein phosphatase inhibitor. 1744 Nov 73