The activity of GSTs is dependent upon a steady supply of GSH from the synthetic enzymes gamma-glutamylcysteine synthetase and glutathione synthetase, as well as the action of specific transporters to remove conjugates of GSH from the cell. The primary role of GSTs is to detoxify xenobiotics by catalyzing the nucleophilic attack by GSH on electrophilic carbon, sulfur, or nitrogen atoms of said nonpolar xenobiotic substrates, thereby preventing their interaction with crucial cellular proteins and nucleic acids. Specifically, the function of GSTs in this role is twofold: to bind both the substrate at the enzyme's hydrophobic "H"-site and GSH at the adjacent, hydrophilic G-site, which together form the active site of the enzyme; and subsequently to activate the thiol group of GSH, enabling the nucleophilic attack upon the substrate. The glutathione molecule binds in a cleft between "N"- and "C"-terminal domains - the catalytically important residues are proposed to reside in the "N"-terminal domain. Both subunits of the GST dimer, whether hetero- or homodimeric in nature, contain a single nonsubstrate binding site, as well as a GSH-binding site. In heterodimeric GST complexes such as those formed by the cytosolic mu and alpha classes, however, the cleft between the two subunits is home to an additional high-affinity nonsubstrate xenobiotic binding site, which may account for the enzymes' ability to form heterodimers.