Inhibition of arabinose 5-phosphate isomerase. An approach to the inhibition of bacterial lipopolysaccharide biosynthesis.
Arabinose 5-phosphate ( A5P ) isomerase is a key enzyme in the biosynthesis of lipopolysaccharide, an essential component of the outer membrane of Gram-negative bacteria. The mechanism of the isomerase is envisioned to involve an enediol intermediate. A series of compounds, which are analogues of the substrates or intermediate, were tested as inhibitors of A5P isomerase with the belief that a good inhibitor would stop bacterial growth or render the cells more susceptible to other antibiotics or natural defenses. In a series of phosphorylated sugars, the order of isomerase inhibitory activity was as follows: aldonic acids greater than alditols greater than aldoses. Nonphosphorylated sugars were much less inhibitory. The best inhibitor was erythronic acid 4-phosphate (54), which had Km/Ki = 29. None of the compounds displayed antibacterial activity in vitro.
D019747:Aldose-Ketose Isomerases; D001089:Arabinose / Q000031:analogs & derivatives; D001419:Bacteria / Q000201:enzymology*; D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000096:biosynthesis*; D012266:Ribose / Q000031:analogs & derivatives / Q000494:pharmacology; D013400:Sugar Acids / Q000494:pharmacology; D013403:Sugar Phosphates / Q000494:pharmacology
D007783:Lactones; D008070:Lipopolysaccharides; D013400:Sugar Acids; D013403:Sugar Phosphates; D012266:Ribose; D001089:Arabinose; D002238:Carbohydrate Epimerases; D019747:Aldose-Ketose Isomerases; C041486:arabinose-5-phosphate isomerase