期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 29, 期 4, 页码 491-494出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/14756366.2013.805757
关键词
Computational chemistry; disulfide reduction; enzyme kinetics; GSSG; inhibition
资金
- National Science Foundation (NSF-CAREER) [MCB-0844478]
- NSF [0947944]
- ACS Project SEED
- NSF S-STEM grant [0806501]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0844478] Funding Source: National Science Foundation
- Direct For Education and Human Resources
- Division Of Undergraduate Education [0806501] Funding Source: National Science Foundation
The activity of glutathione reductase with an unnatural analog of oxidized glutathione was explored. The analog, L-gamma-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.
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