Prolyl isomerases and immunosuppressant drugs

Because of the common property of the PPIases as targets for immunosuppressant drugs, Schreiber renamed the PPIases the immunophilins. This term has come to be the one most commonly applied to these proteins. 

by 1989 it was known that the cytosolic target of each of the three immunosuppressive drugs was a peptidylprolyl isomerase. The mechanism of action of the drugs was at that time unknown, and an attractive hypothesis was that inhibition of PPIase activity was critical 

Shortly after the discovery of calcineurin as the mechanistic key for FK506 and CsA action, the mechanism of action of rapamycin began to unfold. It had already been noted that rapamycin blocked the IL-2 stimulated G1 to S phase transition in T-cells, inhibiting cell division. Treatment of T-cells with rapamycin was found to result in decreased enzymatic activity of several kinases, including p70 S6 kinase (a 70 kDa protein which phosphorylates the S6 protein of the small ribosomal subunit),27-29 and cyclin-dependent kinases of 33 and 34 kDa.30,31 However, in vitro experiments demonstrated that these kinases were not directly inhibited by the FKBP-rapamycin complex. In 1993, two yeast proteins were identified that appeared to be involved in the mechanistic pathway and mutations in these proteins conferred resistance to rapamycin-induced cytotoxicity.32 These proteins were named TORI and TOR2 (targets of rapamycin). 

In 1994 two groups independently and concurrently reported the identification of a protein which interacted with FKBP 12 only in the presence of rapamycin. One of these groups was Schreiber s, who isolated the human protein and named it FRAP, for FKBP and rapamycin associated protein.33 The other group, led by Solomon Snyder at Johns Hopkins, isolated a similar protein from rat brain extracts. They named this protein RAFT, for rapamycin and FKBP target.34 Sequencing demonstrated that these were the mammalian homologues of the yeast TOR proteins. 

---

See also in sourсe #XX -- [ , , , , , ]

---