Specificity of pyridinium inhibitors of the ubiquinone reduction sites in mitochondrial complex I.

The Journal of Biological Chemistry
Hideto MiyoshiY Kodama

Abstract

Dual binding sites for pyridinium-type inhibitors in bovine heart mitochondrial complex I have been proposed (Gluck, M. R., Krueger, M. J., Ramsay, R. R., Sablin, S. O., Singer, T. P., and Nicklas, W. J. (1994) J. Biol. Chem. 269, 3167-3174). The marked biphasic nature of the dose-response curve for inhibition of the enzyme by MP-6(N-methyl-4-[2-(p-tert-butylbenzyl)propyl]pyridinium) makes this compound the first selective inhibitor of the two sites (Miyoshi, H., Inoue, M., Okamoto, S., Ohshima, M., Sakamoto, K., and Iwamura, H. (1997) J. Biol. Chem. 272, 16176-16183). Modifications of the structure of MP-6 show that a tert-butyl group on the benzene ring, a methyl group attached to the pyridine nitrogen atom, para-substitution pattern in the pyridine ring, and the presence of a branched structure in the spacer moiety are important for the selective inhibition. On the basis of the structural specificity, we synthesized a selective inhibitor, MP-24 (N-methyl-4-[2-methyl-2-(p-tert-butylbenzyl)propyl]pyridinium), which elicits greater selectivity. Characterization of the inhibitory behavior of MP-24 provided further strong evidence for the dual binding sites model.

References

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Jan 1, 1985·Annual Review of Biochemistry·Y Hatefi
Oct 11, 1993·FEBS Letters·E EstornellG Lenaz
Jun 27, 1997·The Journal of Biological Chemistry·H MiyoshiH Iwamura

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Citations

May 30, 2001·Advanced Drug Delivery Reviews·I E Scheffler
Apr 28, 2000·European Journal of Biochemistry·K KuwabaraH Miyoshi
Aug 9, 2003·Biochimica Et Biophysica Acta·Takara InoHideto Miyoshi
Jun 18, 2020·Life·Carla FerreiraAlexandre Quintas

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