FK-506-binding proteins from streptomycetes producing immunosuppressive macrolactones of the FK-506 type.
FK-506-binding proteins (FKBPs), which in T cells are supposed to mediate the immunosuppressive effects of the compounds FK-506 and rapamycin, have been isolated from Streptomyces chrysomallus, S. hygroscopicus subsp. ascomyceticus, and S. hygroscopicus. The latter two strains are producers of ascomycin (the ethyl analog of FK-506) and rapamycin, respectively. Like the 12-kDa FKBP in eukaryotic organisms such as humans, bovines, and Saccharomyces cerevisiae, or the FKBPs from gram-positive streptomycetes are peptidyl-prolyl-cis-trans isomerases. Inhibition studies using FK-506, rapamycin, or ascomycin, revealed inhibition of the peptidyl-prolyl cis-trans isomerase activity of the proteins at the nanomolar level, which is in the same range as with eukaryotic FKBPs. The M(r)s of the various FKBPs were 13,500 to 15,000, and they had the same pI of approximately 4.5. The N-terminal sequences of the three FKBPs were nearly identical in the first 20 amino acids. The amino acid sequence deduced from the gene sequence of S. chrysomallus gave a polypeptide of 124 amino acids. The homologies to FKBPs from humans, S. cerevisiae, and Neurospora crassa were 38, 39, and 50% identity in relevant positions, respectively. Significant homology of 38% was also seen with the C-terminal halves of bacterial protein surface antigens like the Mip protein of Legionella pneumophila and the 27-kDa Mip-like protein of Chlamydia trachomatis. In addition, two more open reading frames in Pseudomonas aeruginosa and Neisseria meningitidis of unknown function show regions of homology to the S. chrysomallus FKBP. In contrast to fungi, streptomycetes are resistant to macrolactones. Ascomycin-producing S. hygroscopicus subsp. ascomyceticus excretes the compound almost quantitatively into medium, which indicates that the organism has an efficient self-protection mechanism against its own secondary metabolite.
Pahl
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Institut für Biochemie und Molekulare Biologie, Technische Universität Berlin, Germany.
Keller
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D000591:Amino Acid Isomerases / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification*; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial; D007166:Immunosuppressive Agents / Q000378:metabolism*; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D011090:Polyenes / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D020123:Sirolimus; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; C058028:immunomycin; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus; D016559:Tacrolimus