Inhibition of FKBP rotamase activity by immunosuppressant FK506: Twisted amide surrogate

Michael K. Rosen, Robert F. Standaert, Andrzej Galat, Masashi Nakatsuka, Stuart L. Schreiber

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

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 α-keto amide of FK506 serves as a surrogate for the twisted amide of a bound peptide substrate.

Original languageEnglish (US)
Pages (from-to)863-866
Number of pages4
JournalScience
Volume248
Issue number4957
StatePublished - May 18 1990

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Tacrolimus Binding Proteins
Tacrolimus
Immunosuppressive Agents
Amides
Cyclophilins
Cyclosporine
Peptidylprolyl Isomerase
Enzymes
Catalysis
Transcriptional Activation
T-Lymphocytes
Peptides
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Rosen, M. K., Standaert, R. F., Galat, A., Nakatsuka, M., & Schreiber, S. L. (1990). Inhibition of FKBP rotamase activity by immunosuppressant FK506: Twisted amide surrogate. Science, 248(4957), 863-866.

Inhibition of FKBP rotamase activity by immunosuppressant FK506 : Twisted amide surrogate. / Rosen, Michael K.; Standaert, Robert F.; Galat, Andrzej; Nakatsuka, Masashi; Schreiber, Stuart L.

In: Science, Vol. 248, No. 4957, 18.05.1990, p. 863-866.

Research output: Contribution to journalArticle

Rosen, MK, Standaert, RF, Galat, A, Nakatsuka, M & Schreiber, SL 1990, 'Inhibition of FKBP rotamase activity by immunosuppressant FK506: Twisted amide surrogate', Science, vol. 248, no. 4957, pp. 863-866.
Rosen MK, Standaert RF, Galat A, Nakatsuka M, Schreiber SL. Inhibition of FKBP rotamase activity by immunosuppressant FK506: Twisted amide surrogate. Science. 1990 May 18;248(4957):863-866.
Rosen, Michael K. ; Standaert, Robert F. ; Galat, Andrzej ; Nakatsuka, Masashi ; Schreiber, Stuart L. / Inhibition of FKBP rotamase activity by immunosuppressant FK506 : Twisted amide surrogate. In: Science. 1990 ; Vol. 248, No. 4957. pp. 863-866.
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