Abstract
This article reviews the design and study, in our own laboratory and others, of new steroidal triterpenes with a modified lanosterol or cycloartenol frame. These compounds, along with a number of known analogs with the cholestane skeleton, have been evaluated as reversible or irreversible inhibitors of sterol C24-methyltransferase (SMT) from plants, fungi and protozoa. The SMT catalyzes the C24-methylation reaction involved with the introduction of the C24-methyl group of ergosterol and the C24-ethyl group of sitosterol, cholesterol surrogates that function as essential membrane inserts in many photosynthetic and non-photosynthetic eukaryotic organisms. Sterol side chains constructed with a nitrogen, sulfur, bromine or fluorine atom, altered to possess a methylene cyclopropane group, or elongated to include terminal double or triple bonds are shown to exhibit different in vitro activities toward the SMT which are mirrored in the inhibition potencies detected in the growth response of treated cultured human and plant cells or microbes. Several of the substrate-based analogs surveyed here appear to be taxa-specific compounds acting as mechanism-based inactivators of the SMT, a crucial enzyme not synthesized by animals. Possible mechanisms for the inactivation process and generation of novel products catalyzed by the variant SMTs are discussed.
Highlights
Sterol metabolism is an extremely important area of biochemical differentiation between humans and their pathogenic microbes that might be exploited in the development of antifungal or antiparasitic drugs
Such reactive intermediates are active in covalent bond formation once they enter the transition state coordinate; the resulting positive charge on the intermediate can be captured by an active site nucleophile followed by enzyme inactivation that ends catalysis, [53] thereby ending the production of ergosterol or sitosterol
In order to test the effect of fluorine atom substitution on the electrophillic nature of the enzymatic C24-methylation reaction, we previously reported the kinetic, inhibition and product distribution experiments of 24-fluorocycloartenol 59 assayed with the plant 24SMT [60]
Summary
Sterol metabolism is an extremely important area of biochemical differentiation between humans and their pathogenic microbes that might be exploited in the development of antifungal or antiparasitic drugs. For substrates of fungal or plant 24-SMT, the C20R-chirality and two methyl groups on the terminal double bond (isopropylidene moiety) were shown to be indispensable for productive binding and catalysis [37,38].
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