Rapamycin Immunophilins

Rapamycin is a macrocyclic lactone produced by Streptomyces hygroscopious. This bacterium was originally cultured from a soil sample collected on Easter Island (known locally as Rapa Nui hence the name rapamycin). Parenthetically, rapamycin shares an interesting mode of action with two other antifungal and immunosuppressive compounds, FK506and cyclosporin A. Inside cells, rapamycin first binds to FKBP12, a small protein receptor known as an immunophilin. FKBP12 is not an essential protein but is an important cofactor required for rapamycin to bind and inhibit TOR. 

A new class of immunosuppressive agents called proliferation-signal inhibitors (PSIs) includes sirolimus (rapamycin) and its derivative everolimus. The mechanism of action of PSIs differs from that of the calcineurin inhibitors. PSIs bind the circulating immunophilin FK506-binding protein 12, resulting in an active complex that blocks the molecular target of rapamycin (mTOR). 

Binds to an immunophilin protein to form a complex which inhibits the activation ot the mammalian Target of Rapamycin (mTOR)ulatory kinase. This inhibits T lymphocyte activation and proliferation by IL-2. IL-4, and IL-5. 

Wood MA, Bierer BE. Rapamycin biological and therapeutic effects, binding by immunophilins and molecular targets of action. Perspect Drug Discov Design 1994 2 163-184. 

Studies on the exact mode of action of the unmodified sanglifehrin A (1) by Liu et al. found that 1 inhibits the T cell cycle (G1 phase), mediated by activation of the tumor suppressor gene p53 [21]. Sanglifehrin A (1) is a novel immunosuppressant, which, in addition to CsA, FK506, and rapamycin, represents a fourth class of immunophilin-binding metabolites with a new, as yet undefined mechanism of action [22]. The structural variation now accessible through total and partial synthesis should contribute to understanding of its bio-... 

Immunophiliiis are proteins that participate in T cell activation and bind immunosuppressants such as FK506 and rapamycin. A related group of proteins are the cyclo-philins which bind cyclosporin A. On binding immunosuppressants the immunophilins block T cell 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). 

Sirolimus (rapamycin) is a macrolide compound related to erythromycin and tacrolimus. It binds to the same immunophilin as tacrolimus, but it does not inhibit calcineurin. Sirolimus blocks T-cell activation at a late stage, interfering with the signal from 1L2 receptors and receptors for other cytokines and growth factors, and so blocking the cytokine or growth factor-induced activation of the proliferation cell cycle response [409]. This powerful immunosuppressive... 

Rapamycin (sirolimus) is also a natural product, from a soil organism, which is unrelated to cyclosporin but has similar actions, though binding to a different immunophilins. Tacrolimus is a recently introduced macrolide antibiotic similar to cyclosporin, but appears to have a higher incidence of neurotoxicity and nephrotoxicity. 

Figure 4.9. Schematic representation of immunosuppressant-immunophilin complex interactions. CyPs bind CsA to form a complex in which both components undergo change in structure. This complex binds to, and inhibits, calcineurin (CnA, A subunit CnB, B subunit CaM, camodulin) in a calcium-dependent manner. FK506-binding protein complxes with FK506 or rapamycin (Rapa). FKBP-FK506 also binds calcineurin. The target of FKBP-rapamycin is unknown but is presumed to be different from cacineurin.

Figure 3. Nonimmunosuppressive immunophilin ligands used to probe the mechanism of action of FK506, rapamycin, and cyclosporin A.

Two new immunophilins have recently been discovered which contain both FKBP and cyclophilin domains. A 37 kDa protein isolated from the Jurkat T-cell line was found to bind FK506, rapamycin, and cyclosporin A, all with high affinity.50 FKBP37 contains two FKBP domains and one cyclophilin domain, and also possesses glyceraldehyde 3-phosphate dehydrogenase activity. The 52 kDa protein, isolated from human lymphoid cells, also binds all three immunosuppressant drugs but shows no detectable rotamase activity towards a variety of peptidic substrates.95... 

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