Protein phosphatases immunosuppression

FKBP12 is a member of immunophilin family that has prolyl isomerase activity and is related to the cyclophi-lins in function. FKBP12 binds immunosuppressant molecule FK506 (tacrolimus). The FBKP-FK506 complex inhibits calcineurin, a protein phosphatase, thus blocking signal transduction in the T-lymphocyte... 

Immunosuppressive Agents Protein Phosphatases Ryanodine Receptor... 

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). 

NF-AT transcription factors are targets of immunosuppressive drugs, such as cyclosporin A and FK506, because they inhibit the calcineurin protein phosphatase and gene activation in T cells (see Chapter 7). 

McKeon, F. (1991). When worlds collide immunosuppressants meet protein phosphatases. Cell 66, 823 826. 

Stevastelins A, A3, B, B3, C3, D3 and E3 (Fig. 45) were discovered by Morino et al. in 1996, as immunosuppressants that inhibit dual-specificity protein phosphatases from Penicillium sp.. ... 

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. ... 

Cyclosporine and tacrolimus belong to a class of immunosuppressants called the calcineurin inhibitors. These agents are considered by many to be the cornerstone of medical immunosuppression. The calcineurin inhibitors work by complexingwith cytoplasmic proteins (cyclosporine with cyclophylin and tacrolimus with FK binding protein 12). These complexes then inhibit calcineurin phosphatase, which results in reduced IL-2 gene transcription. The final outcome is a decrease in IL-2 synthesis and a subsequent reduction in T cell activation.7 11 20 21... 

Kiessig et al. studied the interaction of the immunosuppressant drug cyclosporin A and some derivatives to its cellular receptor protein cyclo-philin (26). The cyclophilin-cyclosporin A complex mediates the immunosuppressive action of cyclosporin A by inhibition of the phosphatase calci-neurin. Using ACE in the equilirium-mixture mode, a separation of the cyclophilin-cyclosporin A complex and the unbound cyclophilin was achieved. The approach allowed a qualitative estimation of the binding affinity of cyclosporin A derivatives compared to cyclosporin A. For the calculation of binding constants, electrophoretically mediated microanalysis was applied. 

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. 

The immimosuppressive effect of cyclosporin and FK506 could not initially be explained by these observations. Only with the discovery that cyclosporin and FK506 achieve their immunosuppressive effect via inhibition of calcineurin did it become clear that the immimosuppression is mediated by a complex reaction chain involving calcineurin. It was shown that the complexes of cyclosporin/cyclophilin and FK506/ FK506 binding protein bind to calcineurin and inhibit the phosphatase activity of the latter. 

---