Type II NADH dehydrogenase of the respiratory chain of Plasmodium falciparum and its inhibitors.
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.
Dong
Carolyn K
CK
Department of Immunology and Infectious Disease, Harvard School of Public Health, Building 1, Boston, MA 02115, USA.
Patel
Vishal
V
Yang
Jimmy C
JC
Dvorin
Jeffrey D
JD
Duraisingh
Manoj T
MT
Clardy
Jon
J
Wirth
Dyann F
DF
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004579:Electron Transport; D004583:Electrons; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007215:Indophenol / Q000494:pharmacology; D008956:Models, Chemical; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009861:Onium Compounds / Q000494:pharmacology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D019800:Phenol / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology; D024483:Vitamin K 3 / Q000494:pharmacology
C521526:1-hydroxy-2-dodecyl-4(1H)quinolone; D001713:Biphenyl Compounds; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D009861:Onium Compounds; D015363:Quinolones; C031291:diphenyliodonium; D019800:Phenol; D007215:Indophenol; D024483:Vitamin K 3; D044925:Oxidoreductases Acting on CH-CH Group Donors; D009245:NADH Dehydrogenase