Characterization and inhibition of C-24 sterol methyltransferase from trypanosoma cruzi
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Abstract
Trypanosoma cruzi, the causative agent of Chagas Disease, exhibits reliance on the formation of C-24 alkylated sterols. Therapeutic drug design can exploit this dependence by targeting C-24 sterol methyltransferase (24-SMT). Here, we partially purified 24-SMT from an over expressed e. coli vector and examined the enzymatic reaction kinetically and chemically with varying substrates and inhibitors. The natural substrate was shown to be zymosterol with a KM 40±4 μM of and a kcat of 1.4-min-1 or 0.023-s-1. The suicide substrate, dehydrozymosterol (DHZ) demonstrated a kinact of 0.09-min-1 giving it a partition ratio of 15.56. This conveys a high efficacy of DHZ as a possible chemotherapeutic agent for disrupting the sterol metabolic pathway in Trypanosoma cruzi.