FK506/FKBPs

FK506-FKBP system. The first, by McPherson et al,294 biotinylated FK506 (81) through the secondary hydroxyl in 3% overall yield and used streptavidin-coated magnetic beads for immobilization and after just three rounds of selection, the library converged onto a single clone for FKBPla. 

These two examples, using FK506-FKBP, clearly demonstrate the potential of mRNA display for the isolation of natural product receptors and, like phage display, could be used to determine the target proteins for natural products with no known target or even no known biological activity. 

Tacrolimus (TRL), in the past also named FK506, belongs to the group of macrolides and is produced by a special actinomycete species. TRL binds to its cytosolic receptor FKBP-12, however, it also blocks calcineurin activity and subsequently cytokine synthesis. 

Fe-TPAA Fe(III)-tris[N-(2-pyridylmethyl)-2-aminoethyl] amine Fe-TPEN Fe(II)-tetrakis-N,N,N, N -(2-pyridyl methyl-2-aminoethyl)amine FFA Free fatty acids FGF Fibroblast growth factor FID Flame ionization detector FITC Fluorescein isothiocyanate FKBP FK506-binding protein FLAP 5-lipoxygenase-activating protein... 

Petros AM, Kawai M, Luly JR, Fesik SW. Conformation of two nonimmunosuppressive FK506 analogs when bound to FKBP by isotope-filtered NMR. FEBS Lett 1992 308 309-314. 

Zeng, B.F., MacDonald, J.R., Bann, J.G., Reck, K., Gambee, J.E., Boswell, B.A. and Bachinger, H.P. (1998) Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis-lrans isomerases, is only partially inhibited by FK506. BiochemicalJournal 330, 109-114. 

Wulfing, C., Lombardero, J. and Pluckthun, A. (1994) An Escherichia coli protein consisting of a domain homologous to FK506-binding proteins (FKBP) and a new metal binding motif. Journal of Biological Chemistry 269, 2895-2901. 

Immunophilin is the generic term for a binding protein for an immunosuppressive agent, and all currently known immunophilins belong to the cyclophilin or FKBP families. The two families of immunophilins— like the small molecules they bind—don t have any readily apparent relationship. FKBP12 and CyPA have no sequence similarity, CsA does not inhibit FKBP12, and FK506 does not inhibit CyPA. 

Both NMR and x-ray studies have been done on free FKBP12, CyPA, and a variety of complexes (30). These studies have been reviewed recently, and the remainder of this paper will focus on relatively recent work in the FKBP area (30). Unfortunately, there are no structural studies on the FKBP12-FK506-caldneurin or CyPA-CsA-caldneurin complexes, so our understanding of the interactions is indirect and incomplete. Nevertheless, the outline, if not the complete details, of an answer is apparent. 

FE FKBP female equivalent FK506-binding protein... 

YL Hsieh, J Cai, YT Li, JD Henion, B Ganem. Detection of noncovalent FKBP-FK506 and FKBP-Rapamycin complexes by capillary electrophoresis-mass spectrometry and capillary electrophoresis-tandem mass spectrometry. J Am Soc Mass Spectrom 6 85-90, 1995. 

Another drug whose immunosuppressive action is mediated by the complexation with a cellular protein of the immunophilins is FK506. FK506 binds to proteins of the FKBP family. The complex formed is involved in the inhibition of the phosphatase calcineurin, similar to the mode of action of CsA after binding to cyclophilin. The ACE method was used to detect... 

Tacrolimus (previously known as FK506) is a macrolide antibiotic which is obtained from the fungus Streptomyces tsukubaensis. Tacrolimus binds in-tracellularly to the protein FKBP (FK binding protein) which is distinct from the protein that binds cyclosporine. However both drug-protein complexes associate in a similar way with calcineurin and inhibits its serine/threonine phosphatase activity, although the immunosuppressive potency of tacrolimus is approximately 100 fold higher than that of cyclosporine. 

Cyclophilins and FKBPs are large families of proteins. In E. coli there are two cyclophilin genes, three encoding FK506-binding proteins, and one of... 

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