Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance

David A. Fidock; Takashi Nomura; Angela K. Talley; Roland A. Cooper; Sergey M. Dzekunov; Michael T. Ferdig; Lyann M. B. Ursos; Amar bir Singh Sidhu; Bronwen Naude; Kirk W. Deitsch; Xin-zhuan Su; John C. Wooten; Paul D. Roepe; Thomas E. Wellems

Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance

David A. Fidock, Takashi Nomura, Angela K. Talley, Roland A. Cooper, Sergey M. Dzekunov, Michael T. Ferdig, Lyann M. B. Ursos, Amar bir Singh Sidhu, Bronwen Naude, Kirk W. Deitsch, Xin-zhuan Su, John C. Wooten, Paul D. Roepe, Thomas E. Wellems

Research output: Contribution to journal › Article › peer-review

Abstract

The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harboring a novel K761 mutation point to a central role for the PfCRT protein in CQR. This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations. Mutations in PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on DV pH.

Original language	American English
Pages (from-to)	861-871
Number of pages	11
Journal	Molecular Cell
Volume	6
Issue number	4
State	Published - Oct 1 2000
Externally published	Yes

Funding

We are grateful to Owen Schwartz of the NIAID Biological Imaging Facility for confocal microscopy and Brenda Rae Marshall for editorial assistance. P. D. R. thanks the Burroughs Wellcome Fund, and A. K. T. thanks the Howard Hughes Medical Institute Research Scholars Program for support.

Funders	Funder number
Howard Hughes Medical Institute
National Institute of Allergy and Infectious Diseases	Z01AI000483
Burroughs Wellcome Fund

ASJC Scopus Subject Areas

Molecular Biology
Cell Biology

Keywords

verapamil-reversible chloroquine resistance
point mutations
transmembrane protein
Plasmodium falciparum

Disciplines

Life Sciences
Medicinal Chemistry and Pharmaceutics
Parasitic Diseases
Pharmacology, Toxicology and Environmental Health

Access to Document

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944663/

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Fidock, D. A., Nomura, T., Talley, A. K., Cooper, R. A., Dzekunov, S. M., Ferdig, M. T., Ursos, L. M. B., Sidhu, A. B. S., Naude, B., Deitsch, K. W., Su, X., Wooten, J. C., Roepe, P. D., & Wellems, T. E. (2000). Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance. Molecular Cell, 6(4), 861-871. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944663/

Fidock, DA, Nomura, T, Talley, AK, Cooper, RA, Dzekunov, SM, Ferdig, MT, Ursos, LMB, Sidhu, ABS, Naude, B, Deitsch, KW, Su, X, Wooten, JC, Roepe, PD & Wellems, TE 2000, 'Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance', Molecular Cell, vol. 6, no. 4, pp. 861-871. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2944663/>

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title = "Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance",

abstract = "The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harboring a novel K761 mutation point to a central role for the PfCRT protein in CQR. This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations. Mutations in PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on DV pH.",

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AU - Fidock, David A.

AU - Nomura, Takashi

AU - Talley, Angela K.

AU - Cooper, Roland A.

AU - Dzekunov, Sergey M.

AU - Ferdig, Michael T.

AU - Ursos, Lyann M. B.

AU - Sidhu, Amar bir Singh

AU - Naude, Bronwen

AU - Deitsch, Kirk W.

AU - Su, Xin-zhuan

AU - Wooten, John C.

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AB - The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harboring a novel K761 mutation point to a central role for the PfCRT protein in CQR. This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations. Mutations in PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on DV pH.

KW - verapamil-reversible chloroquine resistance

KW - point mutations

KW - transmembrane protein

KW - Plasmodium falciparum

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ER -

Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance

Abstract

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

Access to Document

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