Quercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1

TitleQuercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1
Publication TypeJournal Article
Year of Publication2011
AuthorsDodson, H. C., Lyda T. A., Chambers J. W., Morris M. T., Christensen K. A., and Morris J. C.
JournalExp Parasitol
Volume127
Pagination423-8
Date PublishedFeb
ISBN Number1090-2449 (Electronic)<br/>0014-4894 (Linking)
Accession Number20971104
KeywordsEnzyme Inhibitors/chemistry/metabolism/*pharmacology, Flavonoids/chemistry/pharmacology, Hexokinase/*antagonists & inhibitors, Microbodies/metabolism, Microscopy, Fluorescence, Pilot Projects, Quercetin/chemistry/metabolism/*pharmacology, Recombinant Proteins/antagonists & inhibitors, Trypanocidal Agents/chemistry/metabolism/*pharmacology, Trypanosoma brucei brucei/*drug effects/enzymology/ultrastructure
Abstract

Hexokinases from the African trypanosome, Trypanosoma brucei, are attractive targets for the development of anti-parasitic drugs, in part because the parasite utilizes glycolysis exclusively for ATP production during the mammalian infection. Here, we have demonstrated that the bioflavanoid quercetin (QCN), a known trypanocide, is a mixed inhibitor of Trypanosoma brucei hexokinase 1 (TbHK1) (IC(50) = 4.1 +/- 0.8muM). Spectroscopic analysis of QCN binding to TbHK1, taking advantage of the intrinsically fluorescent single tryptophan (Trp177) in TbHK1, revealed that QCN quenches emission of Trp177, which is located near the hinge region of the enzyme. ATP similarly quenched Trp177 emission, while glucose had no impact on fluorescence. Supporting the possibility that QCN toxicity is a consequence of inhibition of the essential hexokinase, in live parasites QCN fluorescence localizes to glycosomes, the subcellular home of TbHK1. Additionally, RNAi-mediated silencing of TbHK1 expression expedited QCN induced death, while over-expressing TbHK1 protected trypanosomes from the compound. In summary, these observations support the suggestion that QCN toxicity is in part attributable to inhibition of the essential TbHK1.

Short TitleQuercetin, a fluorescent bioflavanoid, inhibits Trypanosoma brucei hexokinase 1