Type II NADH dehydrogenase of the respiratory chain of Plasmodium falciparum and its inhibitors

Bioorg Med Chem Lett. 2009 Feb 1;19(3):972-5. doi: 10.1016/j.bmcl.2008.11.071. Epub 2008 Nov 24.

Abstract

Plasmodium falciparum NDH2 (pfNDH2) is a non-proton pumping, rotenone-insensitive alternative enzyme to the multi-subunit NADH:ubiquinone oxidoreductases (Complex I) of many other eukaryotes. Recombinantly expressed pfNDH2 prefers coenzyme CoQ(0) as an acceptor substrate, and can also use the artificial electron acceptors, menadione and dichlorophenol-indophenol (DCIP). Previously characterized NDH2 inhibitors, dibenziodolium chloride (DPI), diphenyliodonium chloride (IDP), and 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ) do not inhibit pfNDH2 activity. Here, we provide evidence that HDQ likely targets another P. falciparum mitochondrial enzyme, dihydroorotate dehydrogenase (pfDHOD), which is essential for de novo pyrimidine biosynthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biphenyl Compounds / pharmacology
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Electron Transport*
  • Electrons
  • Enzyme Inhibitors / pharmacology*
  • Indophenol / pharmacology
  • Models, Chemical
  • NADH Dehydrogenase / antagonists & inhibitors*
  • NADH Dehydrogenase / chemistry
  • Onium Compounds / pharmacology
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Phenol / pharmacology
  • Plasmodium falciparum / metabolism*
  • Quinolones / pharmacology
  • Vitamin K 3 / pharmacology

Substances

  • 1-hydroxy-2-dodecyl-4(1H)quinolone
  • Biphenyl Compounds
  • Enzyme Inhibitors
  • Onium Compounds
  • Quinolones
  • diphenyliodonium
  • Phenol
  • Indophenol
  • Vitamin K 3
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase
  • NADH Dehydrogenase