期刊
MOLECULAR AND BIOCHEMICAL PARASITOLOGY
卷 158, 期 2, 页码 202-207出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molbiopara.2007.12.013
关键词
Trypanosoma brucei; hexokinase; lonidamine
Glycolysis is essential to the parasitic protozoan Trypanosoma brucei. The first step in this metabolic pathway is mediated by hexokinase, an enzyme that transfers they-phosphate of ATP to a hexose. The T brucei genome (TREU927/4 GUTat10.1) encodes two hexokinases (TbHK1 and TbHK2) that are 98% identical at the amino acid level. Our previous efforts have revealed that TbHK2 is an important regulator of TbHK1 in procyclic form parasites. Here, we have found through RNAi that TbHK1 is essential to the bloodstream form parasite. Silencing the gene for 4 days reduces cellular hexokinase similar to 60% and leads to parasite death. Additionally, we have found that the recombinant enzyme is inhibited by lonidamine (IC50 = 850 mu M), an anti-cancer drug that targets tumor hexokinases. This agent also inhibits HK activity from whole parasite lysate (IC50 = 965 mu M). Last, lonidamine is toxic to cultured bloodstream form parasites (LD50 = 50 mu M) and procyclic form parasites (LD50 = 180 mu M). Interestingly, overexpression of TbHK1 protects PF parasites from lonidamine. These studies provide genetic evidence that TbHK1 is a valid therapeutic target while identifying a potential molecular target of the anti-trypanosomal agent lonidamine. (c) 2008 Elsevier B.V. All rights reserved.
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