Discovery of an ergosterol-signaling factor that regulates trypanosoma brucei growth
dc.creator | Haubrich, Brad A. (TTU) | |
dc.creator | Singha, Ujjal K. | |
dc.creator | Miller, Matthew B. (TTU) | |
dc.creator | Nes, Craigen R. (TTU) | |
dc.creator | Anyatonwu, Hosanna (TTU) | |
dc.creator | Lecordier, Laurence | |
dc.creator | Patkar, Presheet (TTU) | |
dc.creator | Leaver, David J. (TTU) | |
dc.creator | Villalta, Fernando | |
dc.creator | Vanhollebeke, Benoit | |
dc.creator | Chaudhuri, Minu | |
dc.creator | Nes, W. David (TTU) | |
dc.date.accessioned | 2023-08-31T14:52:49Z | |
dc.date.available | 2023-08-31T14:52:49Z | |
dc.date.issued | 2015 | |
dc.description | © 2015 by the American Society for Biochemistry and Molecular Biology Inc. cc-by | |
dc.description.abstract | Ergosterol biosynthesis and homeostasis in the parasitic protozoan Trypanosoma brucei was analyzed by RNAi silencing and inhibition of sterol C24β -methyltransferase ( TbSMT) and sterol 14α-demethylase [ TbSDM ( TbCYP51)] to explore the functions of sterols in T. brucei growth. Inhibition of the amount or activity of these enzymes depletes ergosterol from cells at <6 fg/cell for procyclic form (PCF) cells or <0.01 fg/cell for bloodstream form (BSF) cells and reduces infectivity in a mouse model of infection. Silencing of Tb SMT expression by RNAi in PCF or BSF in combination with 25-azalanosterol (AZA) inhibited parasite growth and this inhibition was restored completely by adding synergistic cholesterol (7.8 μM from lipid-depleted media) with small amounts of ergosterol (1.2 μM) to the medium. These observations are consistent with the proposed requirement for ergosterol as a signaling factor to spark cell proliferation while imported cholesterol or the endogenously formed cholesta-5,7,24-trienol act as bulk membrane components. To test the potential chemotherapeutic importance of disrupting ergosterol biosynthesis using pairs of mechanismbased inhibitors that block two enzymes in the post-squalene segment, parasites were treated with AZA and itraconazole at 1 μM each (ED50 values) resulting in parasite death . Taken together, our results demonstrate that the ergosterol pathway is a prime drug target for intervention in T. brucei infection. -Haubrich, B. A., U. K. Singha, M. B. Miller, C. R. Nes, H. Anyatonwu, L. Lecordier, P. Patkar, D. J. Leaver, F. Villalta, B. Vanhollebeke, M. Chaudhuri, and W. D. Nes. Discovery of an ergosterol-signaling factor that regulates Trypanosoma brucei growth. J. Lipid Res. 2015. | |
dc.identifier.citation | Haubrich, B.A., Singha, U.K., Miller, M.B., Nes, C.R., Anyatonwu, H., Lecordier, L., Patkar, P., Leaver, D.J., Villalta, F., Vanhollebeke, B., Chaudhuri, M., & Nes, W.D.. 2015. Discovery of an ergosterol-signaling factor that regulates trypanosoma brucei growth. Journal of Lipid Research, 56(2). https://doi.org/10.1194/jlr.M054643 | |
dc.identifier.uri | https://doi.org/10.1194/jlr.M054643 | |
dc.identifier.uri | https://hdl.handle.net/2346/95851 | |
dc.language.iso | eng | |
dc.subject | Anti-parasite drugs | |
dc.subject | Cholesterol | |
dc.subject | Ergosterol biosynthesis | |
dc.subject | Inhibitor | |
dc.subject | Knockdown | |
dc.subject | Ribonucleic acid interference | |
dc.subject | Sparking function | |
dc.title | Discovery of an ergosterol-signaling factor that regulates trypanosoma brucei growth | |
dc.type | Article |
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