The adenosine analog tubercidin inhibits glycolysis in Trypanosoma brucei as revealed by an RNA interference library - PubMed (original) (raw)
. 2003 Nov 21;278(47):46596-600.
doi: 10.1074/jbc.M309320200. Epub 2003 Sep 12.
Affiliations
- PMID: 12972414
- DOI: 10.1074/jbc.M309320200
Free article
The adenosine analog tubercidin inhibits glycolysis in Trypanosoma brucei as revealed by an RNA interference library
Mark E Drew et al. J Biol Chem. 2003.
Free article
Abstract
We used an RNA interference (RNAi) library in a forward genetic selection to study the mechanism of toxicity of tubercidin (7-deazaadenosine) to procyclic Trypanosoma brucei. Following transfection of cells with an RNAi-based genomic library, we used 5 microm tubercidin to select a drug-resistant cell line. Surprisingly, we found in these resistant cells that the hexose transporters had been silenced. We subsequently found that silencing of hexokinase, a glycolytic enzyme, also yielded tubercidin-resistant parasites. These observations suggested that glycolysis could be a target of tubercidin action and that RNAi silencing of glycolytic enzymes was gradual enough to allow the parasites to adapt to alternative sources of energy. Indeed, adaptation of procyclic trypanosomes to a glucose-independent metabolism by reduction of glucose in the culture medium caused tubercidin resistance. High pressure liquid chromatography analysis of glycolytic intermediates from parasites treated with tubercidin showed a dose-dependent increase in concentration of 1,3-bisphosphoglycerate, a substrate of phosphoglycerate kinase. Furthermore, tubercidin triphosphate inhibited recombinant T. brucei phosphoglycerate kinase activity in vitro with an IC50 of 7.5 microm. We conclude that 5 microm tubercidin kills trypanosomes by targeting glycolysis, especially by inhibition of phosphoglycerate kinase.
Similar articles
- The anti-trypanosomal agent lonidamine inhibits Trypanosoma brucei hexokinase 1.
Chambers JW, Fowler ML, Morris MT, Morris JC. Chambers JW, et al. Mol Biochem Parasitol. 2008 Apr;158(2):202-7. doi: 10.1016/j.molbiopara.2007.12.013. Epub 2008 Jan 3. Mol Biochem Parasitol. 2008. PMID: 18262292 - Glycolysis modulates trypanosome glycoprotein expression as revealed by an RNAi library.
Morris JC, Wang Z, Drew ME, Englund PT. Morris JC, et al. EMBO J. 2002 Sep 2;21(17):4429-38. doi: 10.1093/emboj/cdf474. EMBO J. 2002. PMID: 12198145 Free PMC article. - Probing the role of compartmentation of glycolysis in procyclic form Trypanosoma brucei: RNA interference studies of PEX14, hexokinase, and phosphofructokinase.
Kessler PS, Parsons M. Kessler PS, et al. J Biol Chem. 2005 Mar 11;280(10):9030-6. doi: 10.1074/jbc.M412033200. Epub 2005 Jan 6. J Biol Chem. 2005. PMID: 15637070 - Metabolic control analysis of glycolysis in trypanosomes as an approach to improve selectivity and effectiveness of drugs.
Bakker BM, Westerhoff HV, Opperdoes FR, Michels PA. Bakker BM, et al. Mol Biochem Parasitol. 2000 Feb 25;106(1):1-10. doi: 10.1016/s0166-6851(99)00197-8. Mol Biochem Parasitol. 2000. PMID: 10743606 Review. - Energy generation in insect stages of Trypanosoma brucei: metabolism in flux.
Besteiro S, Barrett MP, Rivière L, Bringaud F. Besteiro S, et al. Trends Parasitol. 2005 Apr;21(4):185-91. doi: 10.1016/j.pt.2005.02.008. Trends Parasitol. 2005. PMID: 15780841 Review.
Cited by
- Genetic dissection of drug resistance in trypanosomes.
Alsford S, Kelly JM, Baker N, Horn D. Alsford S, et al. Parasitology. 2013 Oct;140(12):1478-91. doi: 10.1017/S003118201300022X. Epub 2013 Apr 3. Parasitology. 2013. PMID: 23552488 Free PMC article. Review. - 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma brucei.
Mabille D, Cardoso Santos C, Hendrickx R, Claes M, Takac P, Clayton C, Hendrickx S, Hulpia F, Maes L, Van Calenbergh S, Caljon G. Mabille D, et al. Microorganisms. 2021 Apr 13;9(4):826. doi: 10.3390/microorganisms9040826. Microorganisms. 2021. PMID: 33924674 Free PMC article. - A kinetoplastid-specific kinesin is required for cytokinesis and for maintenance of cell morphology in Trypanosoma brucei.
Hu L, Hu H, Li Z. Hu L, et al. Mol Microbiol. 2012 Feb;83(3):565-78. doi: 10.1111/j.1365-2958.2011.07951.x. Epub 2012 Jan 4. Mol Microbiol. 2012. PMID: 22168367 Free PMC article. - Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.
Tyurenkov IN, Kurkin DV, Bakulin DA, Volotova EV, Morkovin EI, Chafeev MA, Karapetian RN. Tyurenkov IN, et al. Front Endocrinol (Lausanne). 2018 Sep 19;9:543. doi: 10.3389/fendo.2018.00543. eCollection 2018. Front Endocrinol (Lausanne). 2018. PMID: 30283402 Free PMC article. - Cloning and Characterization of Trypanosoma congolense and T. vivax Nucleoside Transporters Reveal the Potential of P1-Type Carriers for the Discovery of Broad-Spectrum Nucleoside-Based Therapeutics against Animal African Trypanosomiasis.
Ungogo MA, Aldfer MM, Natto MJ, Zhuang H, Chisholm R, Walsh K, McGee M, Ilbeigi K, Asseri JI, Burchmore RJS, Caljon G, Van Calenbergh S, De Koning HP. Ungogo MA, et al. Int J Mol Sci. 2023 Feb 5;24(4):3144. doi: 10.3390/ijms24043144. Int J Mol Sci. 2023. PMID: 36834557 Free PMC article.