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Interaction of 1-Methyl-4-Phenylpyridinium Ion (MPP+) and Its Analogs with the Rotenone/Piericidin Binding Site of NADH Dehydrogenase

Authors

  • Rona R. Ramsay,

    Corresponding author
    1. Departments of Biochemistry/Biophysics and Pharmacy, University of California, and Molecular Biology Division, Veterans Administration Medical Center, San Francisco, California
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  • Matthew J. Krueger,

    1. Departments of Biochemistry/Biophysics and Pharmacy, University of California, and Molecular Biology Division, Veterans Administration Medical Center, San Francisco, California
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  • Stephen K. Youngster,

    1. Department of Neurology, University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School, Piscataway, New Jersey
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  • Martin R. Gluck,

    1. Department of Neurology, University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School, Piscataway, New Jersey
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  • John E. Casida,

    1. Pesticide Chemistry and Toxicology Laboratory, University of California, Berkeley, California, U.S.A.
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  • Thomas P. Singer

    1. Departments of Biochemistry/Biophysics and Pharmacy, University of California, and Molecular Biology Division, Veterans Administration Medical Center, San Francisco, California
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Address correspondence and reprint requests to Dr. R. R. Ramsay at Molecular Biology Division 151-S, Veterans Administration Medical Center, San Francisco, CA 94121, U.S.A.

Abstract

Abstract: Nigrostriatal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease results from the inhibition of mitochondrial respiration by 1-methyl-4-phenylpyridinium (MPP+). MPP+ blocks electron flow from NADH dehydrogenase to coenzyme Q at or near the same site as do rotenone and piericidin and protects against binding of and loss of activity due to these inhibitors. The 4′-analogs of MPP+ showed increasing affinity for the site with increasing length of alkyl chain, with the lowest Ki, for 4′-heptyl-MPP+, being 6 μM. The 4′-analogs compete with rotenone for the binding site in a concentration-dependent manner. They protect the activity of the enzyme from inhibition by piericidin in parallel to preventing its binding, indicating that the analogs and piericidin bind at the same inhibitory site(s). The optimum protection, however, was afforded by 4′-propyl-MPP+. The lesser protection by the more lipophilic MPP+ analogs with longer alkyl chains may involve a different orientation in the hydrophobic cleft, allowing rotenone and piericidin to still bind even when the pyridinium cation is in a position to interrupt electron flow from NADH to coenzyme Q.

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