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The Remarkable Transport Mechanism of P-Glycoprotein: A Multidrug Transporter

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Human P-glycoprotein (ABCB1) is a primary multidrug transporter located in plasma membranes, that utilizes the energy of ATP hydrolysis to pump toxic xenobiotics out of cells. P-glycoprotein employs a most unusual molecular mechanism to perform this drug transport function. Here we review our work to elucidate the molecular mechanism of drug transport by P-glycoprotein. High level heterologous expression of human P-glycoprotein, in the yeast Saccharomyces cerevisiae, has facilitated biophysical studies in purified proteoliposome preparations. Development of novel spin-labeled transport substrates has allowed for quantitative and rigorous measurements of drug transport in real time by EPR spectroscopy. We have developed a new drug transport model of P-glycoprotein from the results of mutagenic, quantitative thermodynamic and kinetic studies. This model satisfactorily accounts for most of the unusual kinetic, coupling, and physiological features of P-glycoprotein. Additionally, an atomic detail structural model of P-glycoprotein has been devised to place our results within a proper structural context.

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References

  • Al-Shawi, M. K., Polar, M. K., Omote, H., and Figler, R. A. (2003). J. Biol. Chem. 278, 52629–52640.

    Article  CAS  Google Scholar 

  • Al-Shawi, M. K., and Senior, A. E. (1993). J. Biol. Chem. 268, 4197–4206.

    CAS  Google Scholar 

  • Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I., and Gottesman, M. M. (1999). Annu. Rev. Pharmacol. Toxicol. 39, 361–398.

    Article  CAS  Google Scholar 

  • Chang, G. (2003). J. Mol. Biol. 330, 419–430.

    Article  CAS  Google Scholar 

  • Chang, G., and Roth, C. B. (2001). Science 293, 1793–1800.

    Article  CAS  Google Scholar 

  • Choi, K. H., Chen, C. J., Kriegler, M., and Roninson, I. B. (1988). Cell 53, 519–529.

    Article  CAS  Google Scholar 

  • Davidson, A. L., and Chen, J. (2004). Annu. Rev. Biochem. 73, 241–268.

    Article  CAS  Google Scholar 

  • De Rivoyre, M., Bonino, F., Ruel, L., Bidet, M., Therond, P., and Mus-Veteau, I. (2005). FEBS Lett. 579, 1529–1533.

    Article  CAS  Google Scholar 

  • Ecker, G., Huber, M., Schmid, D., and Chiba, P. (1999). Mol. Pharmacol. 56, 791–796.

    CAS  Google Scholar 

  • Exner, O. (1973). Prog. Phys. Org. Chem. 10, 411–482.

    CAS  Google Scholar 

  • Figler, R. A., Omote, H., Nakamoto, R. K., and Al-Shawi, M. K. (2000). Arch. Biochem. Biophys. 376, 34–46.

    Article  CAS  Google Scholar 

  • Flewelling, R. F., and Hubbell, W. L. (1986). Biophys. J. 49, 531–540.

    CAS  Google Scholar 

  • Gottesman, M. M., and Pastan, I. (1993). Annu. Rev. Biochem. 62, 385–427.

    Article  CAS  Google Scholar 

  • Holland, I. B., and Blight, M. A. (1999). J. Mol. Biol. 293, 381–399.

    Article  CAS  Google Scholar 

  • Hung, L. W., Wang, I. X., Nikaido, K., Liu, P. Q., Ames, G. F.-L., and Kim, S. H. (1998). Nature 396, 703–707.

    Article  CAS  Google Scholar 

  • Hyde, S. C., Emsley, P., Hartshorn, M. J., Mimmack, M. M., Gileadi, U., Pearce, S. R., Gallagher, M. P., Gill, D. R., Hubbard, R. E., and Higgins, C. F. (1990). Nature 346, 362–365.

    Article  CAS  Google Scholar 

  • Kioka, N., Tsubota, J., Kakehi, Y., Komano, T., Gottesman, M. M., Pastan, I., and Ueda, K. (1989). Biochem. Biophys. Res. Commun. 162, 224–231.

    Article  CAS  Google Scholar 

  • Lee, S. H., and Altenberg, G. A. (2003a). Biochem. Biophys. Res. Commun. 306, 644–649.

    Article  CAS  Google Scholar 

  • Lee, S. H., and Altenberg, G. A. (2003b). Biochem. J. 370, 357–360.

    Article  CAS  Google Scholar 

  • Leslie, E. M., Deeley, R. G., and Cole, S. P. (2005). Toxicol. Appl. Pharmacol. 204, 216–237.

    Article  CAS  Google Scholar 

  • Litman, T., Skovsgaard, T., and Stein, W. D. (2003). J. Pharmacol. Exp. Ther. 307, 846–853.

    Article  CAS  Google Scholar 

  • Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004a). J. Biol. Chem. 279, 7692–7697.

    Article  CAS  Google Scholar 

  • Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004b). J. Biol. Chem. 279, 18232–18238.

    Article  CAS  Google Scholar 

  • Moiseenkova, V. Y., Hellmich, H. L., and Christensen, B. N. (2003). Biochem. Biophys. Res. Commun. 310, 196–201.

    Article  CAS  Google Scholar 

  • Muller, M., Bakos, E., Welker, E., Varadi, A., Germann, U. A., Gottesman, M. M., Morse, B. S., Roninson, I. B., and Sarkadi, B. (1996). J. Biol. Chem. 271, 1877–1883.

    Article  CAS  Google Scholar 

  • Nakamoto, R. K., Ketchum, C. J., and Al-Shawi, M. K. (1999). Annu. Rev. Biophys. Biomol. Struct. 28, 205–234.

    Article  CAS  Google Scholar 

  • Omote, H., and Al-Shawi, M. K. (2002). J. Biol. Chem. 277, 45688–45694.

    Article  CAS  Google Scholar 

  • Omote, H., Figler, R. A., Polar, M. K., and Al-Shawi, M. K. (2004). Biochemistry 43, 3917–3928.

    Article  CAS  Google Scholar 

  • Pisani, D. F., Rivoyre, M. D., Ruel, L., Bonino, F., Bidet, M., Dechesne, C. A., and Mus-Veteau, I. (2005). Biochem. Biophys. Res. Commun. 331, 552–556.

    Article  CAS  Google Scholar 

  • Polgar, O., and Bates, S. E. (2005). Biochem. Soc. Trans. 33, 241–245.

    Article  CAS  Google Scholar 

  • Ramachandra, M., Ambudkar, S. V., Gottesman, M. M., Pastan, I., and Hrycyna, C. A. (1996). Mol. Biol. Cell 7, 1485–1498.

    CAS  Google Scholar 

  • Ramachandran, G. N., and Sasisekharan, V. (1968). Adv. Protein. Chem. 23, 283–438.

    Article  CAS  Google Scholar 

  • Rao, U. S. (1995). J. Biol. Chem. 270, 6686–6690.

    Article  CAS  Google Scholar 

  • Rao, U. S., and Nuti, S. L. (2003). J. Biol. Chem. 278, 46576–46582.

    Article  CAS  Google Scholar 

  • Romsicki, Y., and Sharom, F. J. (1999). Biochemistry 38, 6887–6896.

    Article  CAS  Google Scholar 

  • Ruth, A., Stein, W. D., Rose, E., and Roninson, I. B. (2001). Biochemistry 40, 4332–4339.

    Article  CAS  Google Scholar 

  • Safa, A. R., Stern, R. K., Choi, K., Agresti, M., Tamai, I., Mehta, N. D., and Roninson, I. B. (1990). Proc. Natl. Acad. Sci. USA 87, 7225–7229.

    CAS  Google Scholar 

  • Sauna, Z. E., and Ambudkar, S. V. (2001). J. Biol. Chem. 276, 11653–11661.

    Article  CAS  Google Scholar 

  • Seelig, A. (1998). Eur. J. Biochem. 251, 252–261.

    Article  CAS  Google Scholar 

  • Seelig, A., Blatter, X. L., and Wohnsland, F. (2000). Int. J. Clin. Pharmacol. Ther. 38, 111–121.

    CAS  Google Scholar 

  • Seelig, A., and Landwojtowicz, E. (2000). Eur. J. Pharm. Sci. 12, 31– 40.

    Article  CAS  Google Scholar 

  • Senior, A. E., Al-Shawi, M. K., and Urbatsch, I. L. (1995a). FEBS Lett. 377, 285–289.

    Article  CAS  Google Scholar 

  • Senior, A. E., Al-Shawi, M. K., and Urbatsch, I. L. (1995b). J. Bioenerg. Biomembr. 27, 31–36.

    Article  CAS  Google Scholar 

  • Shapiro, A. B., Corder, A. B., and Ling, V. (1997). Eur. J. Biochem. 250, 115–121.

    Article  CAS  Google Scholar 

  • Shapiro, A. B., Fox, K., Lam, P., and Ling, V. (1999). Eur. J. Biochem. 259, 841–850.

    Article  CAS  Google Scholar 

  • Shapiro, A. B., and Ling, V. (1995). J. Biol. Chem. 270, 16167–16175.

    Article  CAS  Google Scholar 

  • Shapiro, A. B., and Ling, V. (1997a). Eur. J. Biochem. 250, 122–129.

    Article  CAS  Google Scholar 

  • Shapiro, A. B., and Ling, V. (1997b). Eur. J. Biochem. 250, 130–137.

    Article  CAS  Google Scholar 

  • Shapiro, A. B., and Ling, V. (1998). Eur. J. Biochem. 254, 181–188.

    Article  CAS  Google Scholar 

  • Sharom, F. J. (1997). J. Membr. Biol. 160, 161–175.

    Article  CAS  Google Scholar 

  • Sharom, F. J., Yu, X., and Doige, C. A. (1993). J. Biol. Chem. 268, 24197–24202.

    CAS  Google Scholar 

  • Shilling, R. A., Balakrishnan, L., Shahi, S., Venter, H., and van Veen, H. W. (2003). Int. J. Antimicrob. Agents 22, 200–204.

    Article  CAS  Google Scholar 

  • Stein, W. D., Cardarelli, C., Pastan, I., and Gottesman, M. M. (1994). Mol. Pharmacol. 45, 763–772.

    CAS  Google Scholar 

  • Stenham, D. R., Campbell, J. D., Sansom, M. S., Higgins, C. F., Kerr, I. D., and Linton, K. J. (2003). FASEB J. 17, 2287–2289.

    CAS  Google Scholar 

  • Tu, B. P., and Weissman, J. S. (2002). Mol. Cell. 10, 983–994.

    Article  CAS  Google Scholar 

  • Urbatsch, I. L., Al-Shawi, M. K., and Senior, A. E. (1994). Biochemistry 33, 7069–7076.

    Article  CAS  Google Scholar 

  • Victor, K. G., and Cafiso, D. S. (2001). Biophys. J. 81, 2241–2250.

    Article  CAS  Google Scholar 

  • Yusa, K., and Tsuruo, T. (1989). Cancer Res. 49, 5002–5006.

    CAS  Google Scholar 

  • Zeng, G. F., Pypaert, M., and Slayman, C. L. (2004). J. Biol. Chem. 279, 3003–3013.

    Article  CAS  Google Scholar 

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Author notes

  1. Hiroshi Omote

    Present address: Department of Membrane Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Okayama, 700-8520, Japan

Authors and Affiliations

  1. Department of Molecular Physiology and Biological Physics, University of Virginia Health System, P.O. Box 800736, Charlottesville, Virginia, 22908-0736

    Marwan K. Al-Shawi & Hiroshi Omote

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  1. Marwan K. Al-Shawi
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  2. Hiroshi Omote
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Al-Shawi, M.K., Omote, H. The Remarkable Transport Mechanism of P-Glycoprotein: A Multidrug Transporter. J Bioenerg Biomembr 37, 489–496 (2005). https://doi.org/10.1007/s10863-005-9497-5

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