Recognition of a Cysteine Substrate by E. coliγ-Glutamylcysteine Synthetase Probed by Sulfoximine-based Transition-state Analogue Inhibitors
A series of sulfoximine-based transition-state analogue inhibitors with a varying alkyl side chain was synthesized to probe the recognition of a Cys substrate by E. coliγ-glutamylcysteine synthetase (γ-GCS). The sulfoximines with a small alkyl group (H, methyl, ethyl, propyl, butyl and CH 2 OH) each...
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Published in | Bioscience, biotechnology, and biochemistry Vol. 66; no. 7; pp. 1500 - 1514 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Tokyo
Japan Society for Bioscience, Biotechnology, and Agrochemistry
01.07.2002
Japan Society for Bioscience Biotechnology and Agrochemistry |
Subjects | |
Online Access | Get full text |
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Summary: | A series of sulfoximine-based transition-state analogue inhibitors with a varying alkyl side chain was synthesized to probe the recognition of a Cys substrate by E. coliγ-glutamylcysteine synthetase (γ-GCS). The sulfoximines with a small alkyl group (H, methyl, ethyl, propyl, butyl and CH
2
OH) each served as a slow-binding inhibitor, the sulfoximine with an ethyl being by far the most potent inhibitor to cause facile and irreversible enzyme inhibition. As the size of the side chain changed from an ethyl, the inhibition potency markedly decreased to reduce the overall affinity with concomitant loss in the inactivation rate and with facile enzyme reactivation by dilution. The sulfoximine without a side chain inhibited the enzyme with almost the same potency as that of L-buthionine-(SR)-sulfoximine (BSO). The free energy difference calculated from the inhibition constants indicates that the side chain of Cys was recognized by its size through hydrophobic interaction and contributed almost equally or even more than the carboxy group to the overall binding of Cys in the transition state. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0916-8451 1347-6947 |
DOI: | 10.1271/bbb.66.1500 |