Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.6.3.44 (
P-glycoprotein
)
13,344
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We have recently reported that expression in yeast cells of
P-glycoprotein
(
P-gp
) encoded by the mouse multidrug resistance mdr3 gene (Mdr3) can complement a null ste6 mutation (M. Raymond, P. Gros, M. Whiteway, and D. Y. Thomas, Science 256:232-234, 1992). Here we show that Mdr3 behaves as a fully functional drug transporter in this heterologous expression system. Photolabelling experiments indicate that Mdr3 synthesized in yeast cells binds the drug analog [125I]iodoaryl azidoprazosin, this binding being competed for by vinblastine and tetraphenylphosphonium bromide, two known multidrug resistance drugs. Spheroplasts expressing wild-type Mdr3 (Ser-939) exhibit an ATP-dependent and verapamil-sensitive decreased accumulation of [3H]vinblastine as compared with spheroplasts expressing a mutant form of Mdr3 with impaired transport activity (Phe-939). Expression of Mdr3 in yeast cells can confer resistance to growth inhibition by the antifungal and immunosuppressive agent
FK520
, suggesting that this compound is a substrate for
P-gp
in yeast cells. Replacement of Ser-939 in Mdr3 by a series of amino acid substitutions is shown to modulate both the level of cellular resistance to
FK520
and the mating efficiency of yeast mdr3 transformants. The effects of these mutations on the function of Mdr3 in yeast cells are similar to those observed in mammalian cells with respect to drug resistance and transport, indicating that transport of a-factor and
FK520
in yeast cells is mechanistically similar to drug transport in mammalian cells. The ability of
P-gp
to confer cellular resistance to
FK520
in yeast cells establishes a dominant phenotype that can be assayed for the positive selection of intragenic revertants of
P-gp
inactive mutants, an important tool for the structure-function analysis of mammalian
P-gp
in yeast cells.
...
PMID:Functional expression of P-glycoprotein in Saccharomyces cerevisiae confers cellular resistance to the immunosuppressive and antifungal agent FK520. 750 92
The interactions between the human
P-glycoprotein
(Pgp) and two different types of immunosuppressant drugs known to modulate multidrug resistance in tumor cells have been directly investigated using our newly developed drug-stimulated ATPase assay for Pgp function. The macrolides FK506 and
FK520
stimulate the Pgp-ATPase activity with affinities in the 100 nM range, nearly 10 times higher than that of verapamil, a well known Pgp substrate. On the other hand, the cyclic peptides cyclosporin A and dihydrocyclosporin C do not stimulate the Pgp-ATPase activity at all. They do, however, act as potent competitive inhibitors of verapamil-stimulated Pgp-ATPase activity, with affinity constants in the 20-25 nM range. Thus, although these two classes of immunosuppressant drugs affect the Pgp in different ways, they both probably interact with high affinity at the transported drug binding site(s) of the Pgp, which would explain their ability to resensitize multidrug-resistant cells to the killing action of certain antitumor drugs. Possible implications of these findings for Pgp function, cancer chemotherapy, and immunosuppression are discussed.
...
PMID:Direct demonstration of high affinity interactions of immunosuppressant drugs with the drug binding site of the human P-glycoprotein. 751 63
