Enzymes involved in thiol metabolism

Enzymes involved in thiol metabolism comprise a wide-ranging group of proteins that regulate the synthesis, interconversion, and utilization of sulfur-containing molecules such as glutathione, thioredoxin, and cysteine. Key members of this class include glutathione peroxidase (GPX), glutathione reductase (GSR), thioredoxin reductase (TrxR), and gamma-glutamylcysteine synthetase (GCL), which collectively maintain the cellular redox potential and protect against oxidative damage. These enzymes are vital for neutralizing reactive oxygen species (ROS) and detoxifying xenobiotics through conjugation, particularly in the liver. In the context of cancer, overexpression of thiol metabolism enzymes often confers resistance to oxidative stress and chemotherapy, making them significant targets for drug development aimed at tumor sensitization. Furthermore, unique thiol pathways found in pathogenic organisms, such as the trypanothione system in protozoan parasites like Leishmania and Trypanosoma, offer opportunities for the development of highly selective anti-infective agents that minimize toxicity to human cells. Pharmacological intervention in these pathways, using drugs like buthionine sulfoximine or auranofin, seeks to exploit the critical dependence of diseased cells on thiol-mediated redox homeostasis.

Other names

Thiol metabolic enzymesThiol-dependent enzymesRedox-regulating thiol enzymesEnzymes of sulfur metabolismThiol redox system enzymes

Drugs targeting these enzymes typically function by inhibiting their catalytic activity, thereby disrupting the cellular redox balance and increasing oxidative stress. For instance, inhibitors like buthionine sulfoximine deplete the pool of reduced glutathione (GSH) by targeting GCL, while auranofin inhibits thioredoxin reductase, leading to a loss of redox-regulating capacity. In parasites, targeting unique thiol-based systems such as the trypanothione pathway causes a lethal loss of antioxidant defenses. In oncology, the inhibition of these enzymes is used to sensitize tumor cells to ROS-generating chemotherapeutic agents and radiation by impairing their ability to repair oxidative damage.