Molecule of the Month: Glutathione Transferases

Cells are filled with a confusing jumble of small molecules. Sometimes dangerous molecules get introduced in the mix, and cells need a way to find and remove them. In a first line of defense, enzymes like cytochrome p450 modify slippery carbon-rich toxins, making them more soluble. In a second line of defense, the glutathione transferases attach a convenient handle to unwanted molecules, which is then recognized by the cell’s export machinery.

The trick to making a useful molecular handle is two-fold. First, the handle needs to recognizable, and recognizably different from other molecules in the cell. Glutathione is composed of three familiar amino acids: a glutamate, a cysteine and a glycine. But it won’t be confused with normal peptides because the glutamate is attached in an unusual way, forming the covalent bond through its sidechain. Second, a molecular handle needs an easy chemical way to attach it to other molecules. Glutathione has a sulfur atom at the center (part of the cysteine) that is easily activated and attached to a variety of different molecules.

A collection of just over 20 glutathione transferases work together to scour each cell for toxins. The one shown here is one of the best studied, termed hGSTP1-1 (PDB entry 3gss). These twenty enzymes protect us from many different perils, including toxins made by bacteria and fungi, reactive molecules formed during the cooking of food or smoking, and a variety of environmental pollutants. Because of this, each glutathione transferase typically recognizes a variety of foreign molecules, attaching them all to glutathione. This job is so important that in some cells, such as liver cells, glutathione transferase can make up 10% of the total protein content of the cell!

The process of detoxification can lead to an arms race, where defenses battle with attackers. An example has recently been studied with mosquitoes that carry malaria in Africa. DDT is widely used to control mosquitoes, but DDT-resistant mosquitoes appear in regions of heavy pesticide use. Looking inside these mosquitoes, one of the ways they become resistant is by building a mutant glutathione transferase. Ironically, the mutant replaces a single leucine with a larger phenylalanine, but the change causes a slight refolding of the protein that creates a larger active site that fits the bulky DDT molecule (PDB entries 3zml and 3zmk).