Immunophilins FKBPs

Also see color figure.) Structures for the immunosuppressant, FK506 (tacrolimus). Tacrolimus is a macrolide isolated from Streptomyces tsukubaensis. Shown from left to right in approximately the same orientation are the simple line structure, a stick- structure, and a space-filling structure. The stick and space-filling structures are based on the 3-dimensional structure of the molecule bound to the immunophilin FKBP. Protein data bank designation IFKF. 

Wong PW, Pessah IN. 1997. Noncoplanar PCB 95 alters microsomal calcium transport by an immunophilin FKBP 12-dependent mechanism. Mol Pharmacol 51 693-702. 

Nilsson, A. et al., Increased striatal mRNA and protein levels of the immunophilin FKBP-12 in experimental Parkinson s disease and identification of FKBP-12-binding proteins, J. Proteome Res., 6, 3952, 2007. 

Both tacrolimus and rapamycin (and more recently pimecrolimus or ascomycin) are classified in immunosuppressive macrolides. In the case of tacrolimus and rapamycin, the mechanisms by which they exert immunosuppression are quite different, although both are ligands of the same immunophilin, FKBP-12. Tacrolimus impedes the early phases of the immune signal transduction pathway... 

Macrolides and Related Compounds.- Complex phosphonates continue to be used in the construction of the carbon framework in syntheses of macrocyclic compounds, for example (187), (188), and (189) in syntheses of the immunosuppressant FK-S06, a high affinity ligand for the immunophilin FKBP,94 and the bis-macrolide (-)-colletol,95 respectively. In the case of the immunophilin FKBP intramolecular phosphonate-based olefination is also used as the cyclization step. ... 

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. 

With another immunophilin, FK binding protein (FKBP), experiments were performed using isotope editing of the [U-13C]-labeled inhibitor ascomycin (bound to unlabeled FKBP) [34], as well as by isotope filtering with unlabeled ascomycin derivatives (bound to labeled FKBP) [35],... 

Pharmacology Sirolimus, a macrolide immunosuppressive agent, inhibits both T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (interleukin-2, -4, and -15) stimulation and also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK binding protein-12 (FKBP-12), to generate an immunosuppressive complex. 

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 (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. 

Tacrolimus suppresses peptidyl-prolyl isomerase activity by binding to the immuno-philin FK506-binding protein-12 (FKBP-12), and the tacrolimus-FKBP-12 complex binds to calcineurin and inhibits calcineurin phosphatase activity. As a result, calcineurin is unable to dephosphorylate NFATc and thus its migration to nucleus is blocked where its association with NFATn is necessary for the activation of key cytokine genes. Therefore, its mechanism of action is similar to cyclosporine although tacrolimus binds to a separate set of immunophilins in the cytoplasm. Tacrolimus, like cyclosporine, inhibits the secretion of key cytokines and inhibits T-cell activation (Fig. 4.2). 

Van Duyne, G. D., Standaert, R. F., Karplus, P. A., Schreiber, S. L., and Clardy, J. (1991a). Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex. 

FKBP, for example, the FK506-binding protein is a member of the family of immuno-phUins. Immunophilins are receptor-like small binding proteins that participate in T cell activation. These small proteins have peptidyl-prolyl-isomerase activity. Binding of the complex of FK506 with its FKBP blocks the action of calcineurin, a phosphatase which is involved in T ceU activation. 

Sirolimus is a macrocyclic lactone produced by the bacteria Streptomyces hygroscopicus. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechaitism of action involves formation of a complex with an immunophilin, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirolimus does not affect calcineurin activity but binds to and inhibits the mammahan kinase, target of rapamycin (mTOR.). mTOR is a key enzyme in cell-cycle progression. When inhibited this kinase blocks cell cycle progression at the G1 to S phase transition (Dumont and Su, 1996 Sehgal, 2003). 

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