Naturstoffe als Sonden zum Studium zellulärer Funktionen – Untersuchungen von Immunophilinen

Rosen, Michael K.; Schreiber, Stuart L.

doi:10.1002/ange.19921040406

Cited by 43 publications

(5 citation statements)

References 116 publications

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“…As a consequence, a synergistic effect on the immune system is observed if, for example, 1 is administered simultaneously with either cyclosporin or FK 506,29, 32 which presently dominate clinical immunosuppressive regimens for the treatment of patients after organ transplantation 33. 34…”

Section: Structure and Biological Activity Of The Prodigiosinsmentioning

confidence: 99%

Chemistry and Biology of Roseophilin and the Prodigiosin Alkaloids: A Survey of the Last 2500 Years

2003

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The pyrrole alkaloids of the prodigiosin family make up an unusual chapter in the chemistry of natural products. Owing to the characteristic red color of these secondary metabolites, colonies of the Gram-negative-producing bacteria may strikingly resemble droplets of blood. This phenomenon caused considerable confusion in the past and was likely responsible for many seemingly miraculous (prodigious) events. After the eventual transition from superstition to science, the prodigiosins started to attract considerable attention because of their promising physiological properties. Most interesting are the immunosuppressive activities at doses that are not cytotoxic, in particular since in vivo studies suggest that the prodigiosins act synergistically with cyclosporine A or FK 506, which are presently the dominant drugs in clinical immunosuppressive regimens. Furthermore, the chemistry of the closely related and structurally rather unique alkaloid roseophilin is summarized, a cytotoxic agent that recently became the focal point of many innovative total syntheses.

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Section: Structure and Biological Activity Of The Prodigiosinsmentioning

confidence: 99%

Chemistry and Biology of Roseophilin and the Prodigiosin Alkaloids: A Survey of the Last 2500 Years

2003

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“…1) which binds to an intracellular receptor protein, cyclophilin (Cyp). The binary complex of the drug with this protein inhibits the phosphatase calcineurin, thus blocking all subsequent steps in the immunostimulatory signal transduction pathway of T cells [1]. In view of the use of CsA (Sandimmun ) as a drug to prevent organ transplant rejection and its use in the treatment of other immune-related diseases including psoriasis [2], a study of the bioactive conformations of CsA is of considerable interest for the design of potential analogue drugs with improved action profiles.…”

Section: Introductionmentioning

confidence: 99%

Conformational polymorphism of cyclosporin A

et al. 1994

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“…The FKBP59 previously known as Hsp59, a heatshock protein with PPiase activity, has been detected in Hsp90 steroid receptor complexes by immunoprecipitation analysis (Nadeau et ai, 1993). More recent data indicate that the inhibition of protein phosphatase calcineurin by the CsA-cyclophilin or the FK506-FKBP complex provides evidence for a specific downstream target of the drug-immunophilin complexes and may prompt a search for endogenous ligands of cyclophilin or FKBP that may effect signal transduction regulation (Walsh etai 1992;Rosen and Schreiber, 1992;Schreiber etai, 1992).…”

mentioning

confidence: 99%

Cloning and characterization of ppiB, a Bacillus subtilis gene which encodes a cyclosporine A‐sensitive peptidyl‐prolyl cis‐trans isomerase

Herrler

Bang

Marahiel

1994

Molecular Microbiology

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Sequencing of N-terminal and internal peptide fragments of the purified 17 kDa Bacillus subtilis peptidyl-prolyl cis-trans isomerase (PPIase) revealed sequence identity to conserved regions of a number of eukaryotic and prokaryotic cyclophilins. Using two oligonucleotide primers corresponding to the N-terminus and a highly conserved internal amino acid sequence, polymerase chain reactions (PCR) with B. subtilis genomic DNA were carried out. The resultant PCR fragment of 335 bp was cloned, sequenced and subsequently used as a probe for screening a lambda Zap II gene library of B. subtilis. Two overlapping positive clones of 5 and 7 kb containing the B. subtilis PPIase gene (ppiB), which is 432 bp in length and encodes a protein of 144 amino acid residues, were identified and two distinct transcriptional initiation sites at the 5' end of ppiB were mapped. The entire region (35 kb) between spoVA and serA was recently sequenced in B. subtilis, and an open reading frame (ORF) that encodes a putative peptidyl-prolyl cis-trans isomerase at about 210 degrees on the B. subtilis genetic map was located. This putative PPIase is identical to PPiB. We have overexpressed the ppiB gene in Escherichia coli, purified the encoded protein to apparent homology and shown that it exhibits PPIase activity. In addition, the recombinant PPiB shows a significant inhibition of PPIase activity by cyclosporin A (CsA) at a level comparable to that observed for the B. subtilis enzyme. Interestingly the B. subtilis PPIase shows about 40% identity to eukaryotic PPIases and less similarity to those of Gram-negative bacteria (27-32% identity). Like other interruption mutants of yeast and Neurospora, which lack a functional cyclophilin gene, a B. subtilis mutant containing ppiB::cat, a cat-interrupted copy of ppiB in the chromosome, is viable.

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Naturstoffe als Sonden zum Studium zellulärer Funktionen – Untersuchungen von Immunophilinen

Cited by 43 publications

References 116 publications

Chemistry and Biology of Roseophilin and the Prodigiosin Alkaloids: A Survey of the Last 2500 Years

Chemistry and Biology of Roseophilin and the Prodigiosin Alkaloids: A Survey of the Last 2500 Years

Conformational polymorphism of cyclosporin A

Cloning and characterization of ppiB, a Bacillus subtilis gene which encodes a cyclosporine A‐sensitive peptidyl‐prolyl cis‐trans isomerase

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