Glutaredoxins: Glutathione-Dependent Redox Enzymes with Functions Far Beyond a Simple Thioredoxin Backup System

Abstract

Most cells contain high levels of glutathione and multiple glutaredoxins, which utilize the reducing power of glutathione to catalyze disulfide reductions in the presence of NADPH and glutathione reductase (the glutaredoxin system). Glutaredoxins, like thioredoxins, may operate as dithiol reductants and are involved as alternative pathways in cellular functions such as formation of deoxyribonucleotides for DNA synthesis (by reducing the essential enzyme ribonucleotide reductase), the generation of reduced sulfur (via 3'-phosphoadenylylsulfate reductase), signal transduction, and the defense against oxidative stress. The three dithiol glutaredoxins of E. coli with the active-site sequence CPYC and a glutathione binding site in a thioredoxin/glutaredoxin fold display surprisingly different properties. These include the inducible OxyR-regulated 10-kDa Grx1 or the highly abundant 24-kDa glutathione S-transferase-like Grx2 (with Grx3 it accounts for 1% of total protein). Glutaredoxins uniquely reduce mixed disulfides with glutathione via a monothiol mechanism where only an N-terminal low pKa Cys residue is required, by using their glutathione binding site. Glutaredoxins also catalyze formation of mixed disulfides (glutathionylation), which is an important redox regulatory mechanism, particularly in mammalian cells under oxidative stress conditions, to sense cellular redox potential.