InterPro domain: IPR008554

Glutaredoxins [ 1 , 2 , 3 ], also known as thioltransferases (disulphide reductases), are small proteins of approximately one hundred amino-acid residues which utilise glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system [ 4 ].

Glutaredoxin functions as an electron carrier in the glutathione-dependent synthesis of deoxyribonucleotides by the enzyme ribonucleotide reductase. Like thioredoxin (TRX), which functions in a similar way, glutaredoxin possesses an active centre disulphide bond [ 5 ]. It exists in either a reduced or an oxidized form where the two cysteine residues are linked in an intramolecular disulphide bond. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH -> GSH reductase -> GSH -> GRX -> protein substrates [ 6 , 7 , 8 , 9 ]. By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress.

Glutaredoxin has been sequenced in a variety of species. On the basis of extensive sequence similarity, it has been proposed [ 10 ] that Vaccinia virus protein O2L is most probably a glutaredoxin. Finally, it must be noted that Bacteriophage T4 thioredoxin seems also to be evolutionary related. In position 5 of the pattern T4 thioredoxin has Val instead of Pro.

This family contains several viral glutaredoxins, and many related bacterial and eukaryotic proteins of unknown function. The best characterised member of this family is G4L ( P68460 ) from Vaccinia virus (strain Western Reserve/WR) (VACV), which is necessary for virion morphogenesis and virus replication [ 11 ]. This is a cytomplasmic protein which functions as a shuttle in a redox pathway between membrane-associated E10R and L1R or F9L [ 12 ].

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11. A glutaredoxin, encoded by the G4L gene of vaccinia virus, is essential for virion morphogenesis. J. Virol. 74, 9175-83
12. Vaccinia virus G4L glutaredoxin is an essential intermediate of a cytoplasmic disulfide bond pathway required for virion assembly. J. Virol. 76, 467-72