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J Enzyme Inhib Med Chem. 2014 Aug;29(4):491-4. doi: 10.3109/14756366.2013.805757. Epub 2013 Jul 1.

Glutathione reductase activity with an oxidized methylated glutathione analog.

Author information

1
Department of Chemistry, University of Wisconsin Oshkosh , Oshkosh, WI , USA and.

Abstract

The activity of glutathione reductase with an unnatural analog of oxidized glutathione was explored. The analog, L-γ-glutamyl-2-methyl-L-cysteinyl-glycine disulfide, places an additional methyl group on the alpha position of each of the central cysteine residues, which significantly increases steric bulk near the disulfide bond. Glutathione reductase was completely unable to catalyze the sulfur-sulfur bond reduction of the analog. Additionally, enzyme kinetics experiments indicated that the analog acts as a competitive inhibitor of glutathione reductase. Computational studies confirm that the methylated analog fits within the active site of the enzyme but its disulphide bond geometry is altered, preventing reduction by the enzyme. The substitution of (R)-2-methylcysteine in place of natural (R)-cysteine in peptides constitutes a new strategy for stabilizing disulphide bonds from enzyme-catalyzed degradation.

KEYWORDS:

Computational chemistry; GSSG; disulfide reduction; enzyme kinetics; inhibition

PMID:
23808802
DOI:
10.3109/14756366.2013.805757
[Indexed for MEDLINE]

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