Glutathione transferases--structure and catalytic activity

Area of Science:

• Biochemistry
• Enzymology
• Molecular Biology

Background:

• Glutathione transferases (GSTs) are crucial enzymes involved in the biotransformation of xenobiotics, including drugs and environmental pollutants.
• Multiple GST forms exist across various species (mammals, insects, plants) and have been isolated and characterized.
• Classification of GSTs relies on enzymatic properties, antibody reactions, and structural characteristics.

Purpose of the Study:

• To classify glutathione transferases based on their enzymatic, immunological, and structural properties.
• To investigate the evolutionary relationships among different GST classes.
• To elucidate the substrate specificities and catalytic mechanisms of GSTs.

Main Methods:

• Isolation and characterization of numerous transferases from mammalian tissues, insects, and plants.
• Enzymatic assays, antibody cross-reactivity studies, and primary structure comparisons.
• Analysis of substrate binding sites using homologous series and chiral substrates, coupled with steady-state kinetics.

Main Results:

• Cytosolic mammalian GSTs are grouped into Alpha, Mu, and Pi classes; microsomal GST differs significantly.
• Homologous GST enzyme classes are found in human, rat, and mouse tissues.
• Primary structure comparisons suggest divergent evolution from a common precursor.
• Organic hydroperoxides, epoxides, quinones, and activated alkenes are identified as potential natural substrates, with 4-hydroxyalkenals being particularly effective.
• Kinetic studies support a sequential catalytic mechanism.

Conclusions:

• Glutathione transferases represent a diverse enzyme superfamily with conserved structural and functional roles in xenobiotic metabolism.
• The classification into distinct classes aids in understanding their specific functions and evolutionary history.
• Further research into GSTs can inform strategies for managing drug metabolism and environmental pollutant detoxification.