The Immunosuppressant FK506 Inhibits Amino Acid Import in Saccharomyces cerevisiae

Joseph Heitman, Antonius Koller, Jeannette Kunz, Ruben Henriquez, Anja Schmidt, N. Rao Movva, Michael N. Hall

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

The immunosuppressants cyclosporin A, FK506, and rapamycin inhibit growth of unicellular eukaryotic microorganisms and also block activation of T lymphocytes from multicellular eukaryotes. In vitro, these compounds bind and inhibit two different types of peptidyl-prolyl cis-trans isomerases. Cyclosporin A binds cyclophilins, whereas FK506 and rapamycin bind FK506-binding proteins (FKBPs). Cyclophilins and FKBPs are ubiquitous, abundant, and targeted to multiple cellular compartments, and they may fold proteins in vivo. Previously, a 12-kDa cytoplasmic FKBP was shown to be only one of at least two FK506-sensitive targets in the yeast Saccharomyces cerevisiae. We find that a second FK506-sensitive target is required for amino acid import. Amino acid-auxotrophic yeast strains (trp1 his4 leu2) are FK506 sensitive, whereas prototrophic strains (TRP1 his4 leu2, trp1 HIS4 leu2, and trp1 his4 LEU2) are FK506 resistant. Amino acids added exogenously to the growth medium mitigate FK506 toxicity. FK506 induces GCN4 expression, which is normally induced by amino acid starvation. FK506 inhibits transport of tryptophan, histidine, and leucine into yeast cells. Lastly, several genes encoding proteins involved in amino acid import or biosynthesis confer FK506 resistance. These findings demonstrate that FK506 inhibits amino acid import in yeast cells, most likely by inhibiting amino acid transporters. Amino acid transporters are integral membrane proteins which import extracellular amino acids and constitute a protein family sharing 30 to 35% identity, including eight invariant prolines. Thus, the second FK506-sensitive target in yeast cells may be a proline isomerase that plays a role in folding amino acid transporters during transit through the secretory pathway.

Original languageEnglish
Pages (from-to)5010-5019
Number of pages10
JournalMolecular and Cellular Biology
Volume13
Issue number8
Publication statusPublished - Aug 1993
Externally publishedYes

Fingerprint

Tacrolimus
Immunosuppressive Agents
Saccharomyces cerevisiae
Amino Acids
Tacrolimus Binding Proteins
Amino Acid Transport Systems
Yeasts
Peptidylprolyl Isomerase
Cyclophilins
Sirolimus
tryptophan-leucine
Cyclosporine
Proteins
Secretory Pathway
Growth
Starvation
Eukaryota
Histidine
Proline
Membrane Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Heitman, J., Koller, A., Kunz, J., Henriquez, R., Schmidt, A., Movva, N. R., & Hall, M. N. (1993). The Immunosuppressant FK506 Inhibits Amino Acid Import in Saccharomyces cerevisiae. Molecular and Cellular Biology, 13(8), 5010-5019.

The Immunosuppressant FK506 Inhibits Amino Acid Import in Saccharomyces cerevisiae. / Heitman, Joseph; Koller, Antonius; Kunz, Jeannette; Henriquez, Ruben; Schmidt, Anja; Movva, N. Rao; Hall, Michael N.

In: Molecular and Cellular Biology, Vol. 13, No. 8, 08.1993, p. 5010-5019.

Research output: Contribution to journalArticle

Heitman, J, Koller, A, Kunz, J, Henriquez, R, Schmidt, A, Movva, NR & Hall, MN 1993, 'The Immunosuppressant FK506 Inhibits Amino Acid Import in Saccharomyces cerevisiae', Molecular and Cellular Biology, vol. 13, no. 8, pp. 5010-5019.
Heitman J, Koller A, Kunz J, Henriquez R, Schmidt A, Movva NR et al. The Immunosuppressant FK506 Inhibits Amino Acid Import in Saccharomyces cerevisiae. Molecular and Cellular Biology. 1993 Aug;13(8):5010-5019.
Heitman, Joseph ; Koller, Antonius ; Kunz, Jeannette ; Henriquez, Ruben ; Schmidt, Anja ; Movva, N. Rao ; Hall, Michael N. / The Immunosuppressant FK506 Inhibits Amino Acid Import in Saccharomyces cerevisiae. In: Molecular and Cellular Biology. 1993 ; Vol. 13, No. 8. pp. 5010-5019.
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