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Originally published In Press as doi:10.1074/jbc.M207817200 on September 19, 2002

J. Biol. Chem., Vol. 277, Issue 48, 46809-46821, November 29, 2002
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Candida glabrata ATP-binding Cassette Transporters Cdr1p and Pdh1p Expressed in a Saccharomyces cerevisiae Strain Deficient in Membrane Transporters Show Phosphorylation-dependent Pumping Properties*

Shun-ichi WadaDagger §, Masakazu NiimiDagger ||**, Kyoko Niimi||Dagger Dagger , Ann R. Holmes||Dagger Dagger , Brian C. Monk||Dagger Dagger , Richard D. Cannon||Dagger Dagger , and Yoshimasa UeharaDagger

From the Dagger  Department of Bioactive Molecules, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan and the Dagger Dagger  Department of Oral Sciences and Orthodontics, University of Otago, P.O. Box 647, Dunedin 9001, New Zealand

The expression and drug efflux activity of the ATP binding cassette transporters Cdr1p and Pdh1p are thought to have contributed to the recent increase in the number of fungal infections caused by Candida glabrata. The function of these transporters and their pumping characteristics, however, remain ill defined. We have evaluated the function of Cdr1p and Pdh1p through their heterologous hyperexpression in a Saccharomyces cerevisiae strain deleted in seven major drug efflux transporters to minimize the background drug efflux activity. Although both Cdr1p- and Pdh1p-expressing strains CDR1-AD and PDH1-AD acquired multiple resistances to structurally unrelated compounds, CDR1-AD showed, in most cases, higher levels of resistance than PDH1-AD. CDR1-AD also showed greater rhodamine 6G efflux and resistance to pump inhibitors, although plasma membrane fractions had comparable NTPase activities. These results indicate that Cdr1p makes a larger contribution than Phd1p to the reduced susceptibility of C. glabrata to xenobiotics. Both pump proteins were phosphorylated in a glucose-dependent manner. Whereas the phosphorylation of Cdr1p affected its NTPase activity, the protein kinase A-mediated phosphorylation of Pdh1p, which was necessary for drug efflux, did not. This suggests that phosphorylation of Pdh1p may be required for efficient coupling of NTPase activity with drug efflux.

* This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a Research Fellowship from the Japan Society for the Promotion of Science for Japanese Young Scientists.

Recipient of funding from the Health Science Research Grants for Research on Emerging and Re-emerging Infectious Diseases, Ministry of Health, Labor and Welfare of Japan.

|| Recipient of funding from the Japan Health Sciences Foundation and the Health Research Council of New Zealand.

** To whom correspondence should be addressed. Tel.: 81-3-5285-1111; Fax: 81-3-5285-1272; E-mail: niimi@nih.go.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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