Inhibition of FKBP rotamase activity by immunosuppressant FK506: twisted amide surrogate.
The immunosuppressive agents cyclosporin A and FK506 inhibit the transcription of early T cell activation genes. The binding proteins for cyclosporin A and FK506, cyclophilin and FKBP, respectively, are peptidyl-prolyl-cis-trans isomerases, or rotamases. One proposed mechanism for rotamase catalysis by cyclophilin involves a tetrahedral adduct of an amide carbonyl and an enzyme-bound nucleophile. The potent FKBP rotamase inhibitor FK506 has a highly electrophilic carbonyl that is adjacent to an acyl-pipicolinyl (homoprolyl) amide bond. Such a functional group would be expected to form a stabilized, enzyme-bound tetrahedral adduct. Spectroscopic and chemical evidence reveals that the drug interacts noncovalently with its receptor, suggesting that the alpha-keto amid of FK506 serves as a surrogate for the twisted amide of a bound peptide substrate.
Rosen
M K
MK
Department of Chemistry, Harvard University, Cambridge, MA 02138.
Standaert
R F
RF
Galat
A
A
Nakatsuka
M
M
Schreiber
S L
SL
D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003001:Cloning, Molecular; D003524:Cyclosporins / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression; D007166:Immunosuppressive Agents; D008213:Lymphocyte Activation; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019696:Peptidylprolyl Isomerase; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus
D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus