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KMID : 0545120090190121582
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Journal of Microbiology and Biotechnology
2009 Volume.19 No. 12 p.1582 ~ p.1589
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Inhibitory mechanism of novel inhibitors of UDP-N-acetylglucosamine enolpyruvyl transferase from Haemophilus influenzae
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Jin Bong-Suk
Han Seong-Gu
Lee Won-Kyu
Yu Yeon-Gyu
Ryoo Sung-Weon
Lee Sang-Jae
Suh Se-Won
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Abstract
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Bacterial UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) catalyzes the transfer of enolpyruvate from phosphoenolphyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first step of bacterial cell wall synthesis. We identified thimerosal, thiram, and ebselen as effective inhibitors of Heamophilus influenzae MurA after screening a chemical library that consisted of a wide range of bioactive compounds. When MurA was preincubated with these inhibitors, their 50% inhibitory concentrations (IC50s) were found to range from 0.1 to 0.7 ?M. Particularly, thimerosal suppressed the growth of several different Gram negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium at a concentration range of 1-2 ?g/ml. These inhibitors covalently modified the cysteine residue near the active site of MurA. This modification changed the open conformation of MurA to a more closed configuration, which may have prevented the necessary conformational change from occurring during the enzyme reaction.
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KEYWORD
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Haemophilus influenzae, MurA, cell wall synthesis, Cys117 loop
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