Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design

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dc.creatorKidane, Medhanie E. (TTU)
dc.creatorVanderloop, Boden H. (TTU)
dc.creatorZhou, Wenxu (TTU)
dc.creatorThomas, Crista D. (TTU)
dc.creatorRamos, Emilio (TTU)
dc.creatorSingha, Ujjal
dc.creatorChaudhuri, Minu
dc.creatorNes, W. David (TTU)
dc.date.accessioned2023-08-31T14:52:47Z
dc.date.available2023-08-31T14:52:47Z
dc.date.issued2017
dc.descriptionCopyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc. cc-by
dc.description.abstractErgosterol biosynthesis pathways essential to pathogenic protozoa growth and absent from the human host offer new chokepoint targets. Here, we present characterization and cell-based interference of Acanthamoeba spp sterol 24-/28-methylases (SMTs) that catalyze the committed step in C28- and C29-sterol synthesis. Intriguingly, our kinetic analyses suggest that 24-SMT prefers plant cycloartenol whereas 28-SMT prefers 24(28)-methylene lophenol in similar fashion to the substrate preferences of land plant SMT1 and SMT2. Transition state analog-24(R,S),25-epiminolanosterol (EL) and suicide substrate 26,27-dehydrolanosterol (DHL) differentially inhibited trophozoite growth with IC50 values of 7 nM and 6 µM, respectively, and EL yielded 20-fold higher activity than reference drug voriconazole. Against either SMT assayed with native substrate, EL exhibited tight binding Ki 9 nM. Alternatively, DHL is methylated at C26 by 24-SMT that thereby, generates intermediates that complex and inactivate the enzyme, whereas DHL is not productively bound to 28-SMT. Steroidal inhibitors had no effect on human epithelial kidney cell growth or cholesterol biosynthesis at minimum amoebicidal concentrations. We hypothesize the selective inhibition of Acanthamoeba by steroidal inhibitors representing distinct chemotypes may be an efficient strategy for the development of promising compounds to combat amoeba diseases.—Kidane, M. E., B. H. Vanderloop, W. Zhou, C. D. Thomas, E. Ramos, U. Singha, M. Chaudhuri, and W. D. Nes. Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design.
dc.identifier.citationKidane, M.E., Vanderloop, B.H., Zhou, W., Thomas, C.D., Ramos, E., Singha, U., Chaudhuri, M., & Nes, W.D.. 2017. Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design. Journal of Lipid Research, 58(12). https://doi.org/10.1194/jlr.M079418
dc.identifier.urihttps://doi.org/10.1194/jlr.M079418
dc.identifier.urihttps://hdl.handle.net/2346/95850
dc.language.isoeng
dc.subjectAcanthamoeba
dc.subjectAnti-amoeba drugs
dc.subjectErgosterol biosynthesis inhibitors
dc.subjectPhytosterol biosynthesis
dc.subjectSterol C24-methyltransferase
dc.titleSterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design
dc.typeArticle

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