Immunosuppression, peptidyl

Two structurally unrelated immunosuppressant drugs, cyclosporin A and FK506, have been shown to bind to separate proteins, which have in common the ability to catalyse the interconversion (8) of the cis and trans rotamers of peptidyl-proline bonds of peptide substrates. A profound change in the conformation, and hence the shape and binding properties of the protein, may result. The mechanism of this isomerization appears, on the basis of recent work (Rosen et al., 1990 Van Duyne et al., 1993 Albers et al., 1990), to involve simple twisting about the amide bond, rather than such alternatives as conversion to a C-N single bond by addition of a nucleophile to C=0.y The proteins which catalyse the reaction may be... 

Siekierka, JJ., Hung, SH., Poe, M., Lin, CS., and Sigal, NH. (1989). A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct ftom cyclophilin. Nature 341, 755-757. 

The protein phosphatase calcineurin was of particular interest since it mediates the immunosuppressive effect of the pharmaceuticals cyclosporin and FK506, often used in organ and tissue transplantations. The biochemical point of application of both pharmaceuticals was unclear for a long time. In initial experiments, it was found that cyclosporin and FK506 bind specifically to two proteins known as cyclophilin and FK506 binding protein, respectively. Both proteins function as peptidyl prolyl cis/trans isome-rases (review Fischer, 1994). 

Tacrolimus (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidyl-prolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein (FKBP). Both complexes inhibit calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT. 

Harding MW, Galat A, Uehling DE, Schreiber SL (1989) A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerise. Nature 341 758-760... 

The search for a common mechanism of action cf the immunosuppressive drugs cyclosporin (CsA) (7)and FK-506 (8)highlights another possibility in which the drug was I discovaed by screening in cellular or in vivo models but the exact mechanism or site of I action is unknown (157). Using the active mol-I ecules, cyclophilin (CyP) and the FK binding protein (FKBP)were identified as the specific receptors for cyclosporin and FK-506, respec-I lively. These binding proteins were discovered to be distinct and inhibitor-specific cis-trans peptidyl-prolyl isomerases that catalyze the... 

Conformational restriction played an important role in the discovery that water induces the bioactive conformation of CsA. Cyclosporin A (Sandimmune , CsA, (23.37), Fig. 23.7), is a major drug for preventing rejection of transplanted human organs and has been the subject of many synthetic, conformational and mechanism of action studies. To produce immunosuppression, CsA first binds to cyclophilin A (CyP A), a peptidyl prolyl cis-trans isomerase (PPIase), to form the CsA-CyP complex, which then binds to and inhibits calcineuiin (CaN), a calmodulin-dependent serine/threonine protein phosphatase, thereby inhibiting interleukin-2 (IL-2) synthesis. ... 

H., and Uesugi, M. (2011) Marine natural product aurilide activates the OPAl-mediated apoptosis by binding to prohibitin. Chem. Biol, 18, 131-139. Harding, M.W., Galat, A., Uehling, D.E., and Schreiber, S.L. (1989) A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature, 341, 758-760,... 

Siekierka JJ, Hung SHY, Poe M, Lin CS, Sigal NH. A cytosolic binding protein for (he immunosuppressant FK506 has peptidyl prolylisomerase activity but is distinct from... 

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