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

Rona R. Ramsay*, Matthew J. Krueger, Stephen K. Youngster, Martin R. Gluck, John E. Casida, Thomas P. Singer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

184 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1184-1190
Number of pages7
JournalJournal of Neurochemistry
Volume56
Issue number4
DOIs
Publication statusPublished - 1 Jan 1991

Keywords

  • 1‐Methyl‐4‐phenylpyridinium
  • 1‐Methyl‐4‐phenylpyridinium analogs
  • Mitochondrial oxidation
  • NADH dehydrogenase
  • Piericidin
  • Rotenone

Fingerprint

Dive into the research topics of 'Interaction of 1‐Methyl‐4‐Phenylpyridinium Ion (MPP+) and Its Analogs with the Rotenone/Piericidin Binding Site of NADH Dehydrogenase'. Together they form a unique fingerprint.

Cite this