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چکیده
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The glyoxalase system catalyzes the glutathione-dependent conversion of toxic methylglyoxal to D-lactate. The system consists of two enzymes, glyoxalase I (GlxI) and glyoxalase II. GlxI converts a hemithioacetal, formed from methylglyoxal and glutathione, to S-D-lactoylglutathione, whereas glyoxalase II converts the latter to D-lactate and glutathione. The catalytic mechanism of GlxI has been studied by two different groups [1,2]. In general, it is accepted that the mechanism is initiated by abstracting a proton from substrate and then the reaction proceeds via an enediolate intermediate. Based on the X-ray structure of GlxI [2], the proton can be abstracted either by Glu172 or Glu99. Also, Glu172 and Glu99 are in best positions to abstract proton from S and R diastereomers of substrate, respectively. In the active site of this enzyme the Glu172 and Glu99 are trans to each other, but they are not coordinated symmetrically to Zn atom. Glu172 is displaced from Zn atom (the Zn–O distance is 3.3 Å). In this work, we look for a reasonable mechanism by hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, including full account of the surrounding protein.
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