A QM/MM study of catalytic mechanism of human Glyoxalase I

The glyoxalase system catalyzes the gluta thione-depe ndent conv ersion of tox ic methylglyoxal to D-lactate. The system consists of two enzymes, glyoxalase I (GlxI) and glyoxalase II. GlxI converts a hem ithioacetal, formed from methylglyoxal and glutathione, to S-D-lactoylglutathione, whereas glyoxalase II converts the latter to D-lactate and glutathione.The c atalytic mechanism of G lxI has been studied by two different groups [۱ ,۲]. In general, it is acc epted that the mechanis m is initiated by abstracting a proton from substrate and th en the reacti on proceeds via an enediolate interm ediate. Bas ed on the X-ray structure of GlxI [۲ ], the proton can be abstracted eit her by Glu۱ ۷۲ or Glu۹۹. Also, Glu۱۷۲ and G lu۹۹ are in best positi ons to abstract proton fr om S and R diastereomers of substr ate, respecti vely. In the active site of this enzyme the Glu۱۷۲ and Glu۹۹ are trans to each other, but they are not coordinated symmetrically to Zn atom. Glu۱۷۲ is displaced from Zn atom (the Zn–O distance is ۳.۳ 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.

کلیدواژه ها:

Glyox alase ، QM/MM ، Reaction mechanis m