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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Dong, Carolyn K.¹  Patel, Vishal^1,2  Yang, Jimmy C.^2,3,4  Dvorin, Jeffrey D.^1,5  Duraisingh, Manoj T.¹  Clardy, Jon^2,3,4  Wirth, Dyann F.^1,3,4 

[1] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[3] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA

[4] MIT, Infect Dis Initiat, Cambridge, MA 02142 USA

[5] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

关键词: Type II NADH dehydrogenase;    NDH2;    Dibenziodolium chloride;    DPI;    Diphenyliodonium chloride;    IDP;    1-Hydroxy-2-dodecyl-4(1H)quinolone;    HDQ;    Dihydroorotate dehydrogenase;    DHOD;    Ubiquinone;    CoQ;    CoQn;   

DOI  :  10.1016/j.bmcl.2008.11.071

来源: Elsevier

【 摘 要 】

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. (C) 2008 Elsevier Ltd. All rights reserved.

【 授权许可】

Free