Calcineurin-FKBP-Inhibitor complexes

Example of Scheme C Inhibition of Calcineurin by FKBP-Inhibitor Complexes... 

Figure 6.17 Cartoon depicting the interactions of FKBP with inhibitor and the subsequent binding of the FKBP Inhibitor binary complex to the enzyme calcineurin (E).

Addition of the L-732,531 FKBP binary complex to a calcineurin activity assay resulted in increasingly nonlinear progress curves with increasing binary complex concentration. The htting of the data to Equation (6.3) revealed an inhibitor concentration effect on v-, as well as on vs and obs, consistent with a two-step mechanism of inhibition as in scheme C of Figure 6.3. Salowe and Hermes analyzed the concentration-response effects of the binary complex on v, and determined an IC50 of 0.90 pM that, after correction for I.S I/A (assuming competitive inhibition), yielded a A) value for the inhibitor encounter complex of 625 nM. 

Sirohmus is a macrocychc lactone produced by the bacteria Streptomyces hygroscopious. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechanism of action involves formation of a complex with an immunophiUn, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirohmus does not affect calcineurin activity but binds to and inhibits the mammalian 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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