The glmS riboswitch is unique among gene-regulating
riboswitches and catalytic RNAs. This is because its own metabolite,
glucosamine-6-phosphate (GlcN6P), binds to the riboswitch and catalytically
participates in the RNA self-cleavage reaction, thereby providing
a novel negative feedback mechanism. Given that a number of pathogens
harbor the glmS riboswitch, artificial actuators
of this potential RNA target are of great interest. Structural/kinetic
studies point to the 2-amino and 6-phosphate ester functionalities
in GlcN6P as being crucial for this actuation. As a first step toward
developing artificial actuators, we have synthesized a series of nine
GlcN6P analogs bearing phosphatase-inert surrogates in place of the
natural phosphate ester. Self-cleavage assays with the Bacillus cereusglmS riboswitch
give a broad SAR. Two analogs display significant activity, namely,
the 6-deoxy-6-phosphonomethyl analog (5) and the 6-O-malonyl ether (13). Kinetic profiles show
a 22-fold and a 27-fold higher catalytic efficiency, respectively,
for these analogs vs glucosamine (GlcN). Given their nonhydrolyzable
phosphate surrogate functionalities, these analogs are arguably the
most robust artificial glmS riboswitch actuators
yet reported. Interestingly, the malonyl ether (13, extra
O atom) is much more effective than the simple malonate (17), and the “sterically true” phosphonate (5) is far superior to the chain-truncated (7) or chain-extended
(11) analogs, suggesting that positioning via Mg coordination
is important for activity. Docking results are consistent with this
view. Indeed, the viability of the phosphonate and 6-O-malonyl ether
mimics of GlcN6P points to a potential new strategy for artificial
actuation of the glmS riboswitch in a biological
setting, wherein phosphatase-resistance is paramount.
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