Glucosamine 6-phosphate synthetase (glmS) catalyzes the first committed step of bacterial cell wall biosynthesis, producing glucosamine 6-phosphate (GlcN6P) from fructose 6-phosphate (F6P). Recently a gene-regulating riboswitch has been identified, residing in the 5'-untranslated region of glmS mRNA. Specifically the glmS riboswitch undergoes a self-cleavage reaction that is facilitated by gene's metabolic product GlcN6P, acting a coenzyme, thereby providing a feedback mechanism of genetic control. Given that a number of human pathogens harbor the glmS riboswitch, fundamental studies directed at artificial actuators of this potential RNA target are in order. Structural and kinetic studies point to the 2-amino and 6-phosphate ester functionalities in GlcN6P as being important for this actuation. As a first step toward the development of novel antimicrobials, we have synthesized a series of GlcN6P analogues, bearing phosphatase-inert surrogates in place of the natural phosphate ester functionality. The self-cleavage assay identified two such compounds that display significant coenzyme activity; namely those bearing a 6-phosphonomethyl group or a 6-O-malonyl ether. Kinetic profiles show a 22-fold and a 27-fold higher catalytic efficiency, respectively, for these two analogues than is observed with glucosamine. Details of the synthesis and observed SAR across the series of GlcN6P analogues will be presented.                                                       

Artificial actuators for the bacterial <i>glmS</i> riboswitch

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Artificial actuators for the bacterial glmS riboswitch