Document Detail

Probing the stereochemistry of the active site of gamma-glutamyl transpeptidase using sulfur derivatives of l-glutamic acid.
MedLine Citation:
PMID:  14737648     Owner:  NLM     Status:  MEDLINE    
Gamma-glutamyl transpeptidase (GGT) catalyses the transfer of a gamma-glutamyl moiety from a donor substrate to different acceptors, such as amino acids and water. GGT is known to display relatively low stereospecificity with respect to the alpha-stereocentre of its donor substrates. In this study we have studied its stereospecificity with respect to the stereocentre at the delta-position of different analogues of L-glutamic acid. Notably, L-methionine sulfoxide is well-recognised whereas L-methionine sulfone and L-methionine sulfoximine are not. Furthermore, when the synthetic gamma-diastereoisomers of L-methionine sulfoxide were separated and tested, it was discovered that GGT shows remarkable stereospecificity at the gamma-position, binding the S(C)S(S) diastereoisomer with a K(i) of 3.5 mM, whereas the S(C)R(S) diastereoisomer is not recognised. Finally, using a sulfoxide as a new pharmacophore for GGT, we have synthesized and tested an analogue of glutathione to obtain a very promising competitive inhibitor with a K(i) of (53 +/- 3) microM.
Christian Lherbet; Jeffrey W Keillor
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-12-02
Journal Detail:
Title:  Organic & biomolecular chemistry     Volume:  2     ISSN:  1477-0520     ISO Abbreviation:  Org. Biomol. Chem.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-22     Completed Date:  2004-04-01     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  101154995     Medline TA:  Org Biomol Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  238-45     Citation Subset:  IM    
C. P. 6128, Succ. Centre-ville, Montréal, Québec H3C 3J7, Canada.
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MeSH Terms
Binding Sites
Binding, Competitive
Enzyme Inhibitors / chemistry,  metabolism,  pharmacology
Glutamic Acid / analogs & derivatives*,  metabolism
Glutathione / analogs & derivatives
Sulfoxides / chemistry,  metabolism,  pharmacology
gamma-Glutamyltransferase / antagonists & inhibitors,  chemistry*,  metabolism
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Sulfoxides; 56-86-0/Glutamic Acid; 70-18-8/Glutathione; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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