6t37
Pseudomonas aeruginosa RmlA in complex with allosteric inhibitor
Structural highlights
FunctionQ9HU22_PSEAE Catalyzes the formation of dTDP-glucose, from dTTP and glucose 1-phosphate, as well as its pyrophosphorolysis (By similarity).[RuleBase:RU003706] Publication Abstract from PubMedThe monosaccharide l-Rhamnose is an important component of bacterial cell walls. The first step in the l-rhamnose biosynthetic pathway is catalysed by glucose-1-phosphate thymidylyltransferase (RmlA), which condenses glucose-1-phosphate (Glu-1-P) with deoxythymidine triphosphate (dTTP) to yield dTDP-d-glucose. In addition to the active site where catalysis of this reaction occurs, RmlA has an allosteric site that is important for its function. Building on previous reports, SAR studies have explored further the allosteric site, leading to the identification of very potent P. aeruginosa RmlA inhibitors. Modification at the C6-NH2 of the inhibitor's pyrimidinedione core structure was tolerated. X-ray crystallographic analysis of the complexes of P. aeruginosa RmlA with the novel analogues revealed that C6-aminoalkyl substituents can be used to position a modifiable amine just outside the allosteric pocket. This opens up the possibility of linking a siderophore to this class of inhibitor with the goal of enhancing bacterial cell wall permeability. Next generation Glucose-1-phosphate thymidylyltransferase (RmlA) inhibitors: An extended SAR study to direct future design.,Xiao G, Alphey MS, Tran F, Pirrie L, Milbeo P, Zhou Y, Bickel JK, Kempf O, Kempf K, Naismith JH, Westwood NJ Bioorg Med Chem. 2021 Nov 15;50:116477. doi: 10.1016/j.bmc.2021.116477. Epub 2021, Oct 16. PMID:34757294[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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