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

ABSTRACT: Ergosterol 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 acti

SUBMITTER: Kidane ME 

PROVIDER: S-EPMC5711494 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature