Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Inhibitory Mechanism of Novel Inhibitors of UDP-N-Acetylglucosamine Enolpyruvyl Transferase from Haemophilus influenzae

  • Jin, Bong-Suk (Department of Chemistry, Kookmin University) ;
  • Han, Seong-Gu (Department of Chemistry, Kookmin University) ;
  • Lee, Won-Kyu (Department of Chemistry, Kookmin University) ;
  • Ryoo, Sung-Weon (Department of Microbiology, Korean Institute of Tuberculosis) ;
  • Lee, Sang-Jae (School of Chemistry and Molecular Engineering, Seoul National University) ;
  • Suh, Se-Won (School of Chemistry and Molecular Engineering, Seoul National University) ;
  • Yu, Yeon-Gyu (Department of Chemistry, Kookmin University)
  • Published : 2009.12.31
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Abstract

Bacterial UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (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 Haemophilus influenzae MurA by screening a chemical library that consisted of a wide range of bioactive compounds. When MurA was preincubated with these inhibitors, their 50% inhibitory concentrations ($IC_{50}s$) were found to range from 0.1 to $0.7\;{\mu}M$. In particular, thimerosal suppressed the growth of several different Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhimurium at a concentration range of $1-2\;{\mu}g/ml$. 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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References

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