Catalytic Mechanism of Class A β-Lactamase. I. The Role of Glu166 and Ser130 in the Deacylation Reaction

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概要

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• The tetrahedral intermediate formation process, which is the first step in the deacylation reaction by class A β-lactamase, was investigated by the ab initio molecular orbital method. In this study, benzyl penicillin was used as the substrate. From the results of our molecular dynamics study of the structure of β-lactam antibiotics-β-lactamase complex, the substrate, Ser70,Lys73,Ser130,Glu166 and a water molecule for the deacylation reaction were considered for construction of a model for calculation. The calculation results indicated that Glu166 plays a role in holding a water molecule, which is necessary for the deacylation reaction, and that the hydrogen bond network among Lys73Nζ, Ser130Oγ, and the carboxy group of the β-lactam antibiotics was formed by the up-take of β-lactam antibiotics by β-lactamase. The activation energy for this reaction was 33.3 kcal/mol, and it is very likely that the reaction occurred at body temperature. Subsequent calculation results obtained by using the model excluding Ser130 and the carboxyl group of the substrate indicated that the activation energy for this reaction was 40.8 kcal/mol, which is 7.5 kcal/mol higher than that of the previous reaction. It was found that the hydrogen bond network plays an imortant role in decreasing the activation energy for the tetrahedral intermediate formation reaction. Lys73Nζ, which is located at the edge of the hydrogen bond network, played a role in forming a hydrogen bond with Glu166Oε in order to help the deacylation reaction. The role of amino acid residues around the active site of class A β-lactamase was also discussed.

• 公益社団法人日本薬学会の論文
• 2000-04-01

著者

• HOSHINO Tyuji

  Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University

• HATA Masayuki

  Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University

• Fujii Y

  Department Of Analytical Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University

• Hoshino T

  Department Of Physical Chemistry Graduate School Of Pharmaceutical Sciences Chiba University

• Hoshino Tyuji

  Department Of Physical Chemistry Graduate School Of Pharmaceutical Sciences Chiba University

• Tsuda M

  Chiba Univ. Chiba Jpn

• Tsuda Minoru

  Laboratory Of Biophysical Chemistry Faculty Of Pharmaceutical Sciences Chiba University

• Tsuda Minoru

  Laboratory Of Physical Chemistry Pharmaceutical Sciences Chiba University

• Tsuda Minoru

  Laboratory Of Bio-physical Chemistry Faculty Of Pharmaceutical Sciences Chiba University

• Hata M

  Department Of Physical Chemistry Graduate School Of Pharmaceutical Sciences Chiba University

• Hata Masayuki

  Laboratory Of Food Chemistry College Of Agriculture

• HOSHINO Tyuji

  Laboratory of Physical Chemistry, Faculty of Pharmaceutical Sciences, Chiba University

• FUJII Yasuyuki

  Laboratory of Physical Chemistry, Faculty of Pharmaceutical Sciences, Chiba University

• ISHII Miho

  Laboratory of Physical Chemistry, Faculty of Pharmaceutical Sciences, Chiba University

• Ishii M

  Department Of Physical Chemistry Graduate School Of Pharmaceutical Sciences Chiba University

• Mitsui Ikuo

  New Product Research Laboratories Iv Daiichi Pharmaceitucal Co. Ltd.

• Fujii Youichi

  Fac. Of Pharmaceutical Sciences Hokuriku Univ.

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