67532-84-7Relevant academic research and scientific papers
INHIBITORS OF DXP SYNTHASE AND METHODS OF USE THEREOF
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Paragraph 0197; 0198, (2015/09/22)
Novel inhibitors of DXP synthase and methods of use thereof are disclosed.
DXP synthase-catalyzed c-n bond formation: Nitroso substrate specificity studies guide selective inhibitor design
Morris, Francine,Vierling, Ryan,Boucher, Lauren,Bosch, Juergen,Freel Meyers, Caren L.
, p. 1309 - 1315 (2013/08/23)
1-Deoxy-D-xylulose 5-phosphate (DXP) synthase catalyzes the first step in the nonmammalian isoprenoid biosynthetic pathway to form DXP from pyruvate and D-glyceraldehyde 3-phosphate (D-GAP) in a thiamin diphosphate-dependent manner. Its unique structure and mechanism distinguish DXP synthase from its homologues and suggest that it should be pursued as an anti-infective drug target. However, few reports describe any development of selective inhibitors of this enzyme. Here, we reveal that DXP synthase catalyzes C-N bond formation and exploit aromatic nitroso substrates as active site probes. Substrate specificity studies reveal a high affinity of DXP synthase for aromatic nitroso substrates compared to the related ThDP-dependent enzyme pyruvate dehydrogenase (PDH). Results from inhibition and mutagenesis studies indicate that nitroso substrates bind to E. coli DXP synthase in a manner distinct from that of D-GAP. Our results suggest that the incorporation of aryl acceptor substrate mimics into unnatural bisubstrate analogues will impart selectivity to DXP synthase inhibitors. As a proof of concept, we show selective inhibition of DXP synthase by benzylacetylphosphonate (BnAP).
