Abstract
Current progress on the mechanism and substrate recognition by sterol methyl transferase (SMT), the role of mechanism-based inactivators, other inhibitors of SMT action to probe catalysis and phytosterol synthesis is reported. SMT is a membrane-bound enzyme which catalyzes the coupled C-methylation-deprotonation reaction of sterol acceptor molecules generating the 24-alkyl sterol side chains of fungal ergosterol and plant sitosterol. This C-methylation step can be rate-limiting in the post-lanosterol (fungal) or post-cycloartenol (plant) pathways. A series of sterol analogs designed to impair SMT activity irreversibly have provided deep insight into the C-methylation reaction and topography of the SMT active site and as reviewed provide leads for the development of antifungal agents.
Highlights
C-methylation of the sterol side chain at C-24, is an important area of biochemical difference between animals and fungi, as well as plants, that can be exploited in the development of new antifungal agents and engineered to generate value-added traits in crops
Compound 41 was tested as an inhibitor of soybean SMT1 and found to be a noncompetitive inhibitor with a Ki value of 55 nM and when added to the sterol methyl transferase (SMT) assay it was not time-dependent [45]. These results suggest that 41 can inhibit SMT via ionic interactions according to path c (Scheme 5)
The unique aspect of the catalysis is the C-methylation of C-26 rather than C-24 which was anticipated [6] and which occurs in the case of 43 [48]
Summary
C-methylation of the sterol side chain at C-24, is an important area of biochemical difference between animals and fungi, as well as plants, that can be exploited in the development of new antifungal agents and engineered to generate value-added traits in crops. The addition of one or two carbon atoms at C-24 involves either a single or double methylation, and distinct mechanisms operate variably in nature These SMTs have catalytic activities that can create diversity at the level of side chain stereochemistry and function. In vascular plants and many fungi such as Pneumocystis carinii, the product of the SMT1 catalyzed reaction can be processed to be the substrate of SMT2 that controls the ratio of 24methyl to 24-ethyl ∆5-sterols. Down-regulation of vascular plant SMT by sitosterol, but not by ergosterol or cholesterol and in the case of yeast SMT by ergosterol but not by sitosterol or cholesterol, suggest plant/fungal-specific membrane inserts can feed-back and modulate the postlanosterol/cycloartenol synthetic pathway (Table 1) [6].
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