| Probing the stereochemistry of the active site of gamma-glutamyl transpeptidase using sulfur derivatives of l-glutamic acid. | |
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MedLine Citation:
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PMID: 14737648 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Christian Lherbet; Jeffrey W Keillor |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2003-12-02 |
Journal Detail:
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Title: Organic & biomolecular chemistry Volume: 2 ISSN: 1477-0520 ISO Abbreviation: Org. Biomol. Chem. Publication Date: 2004 Jan |
Date Detail:
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Created Date: 2004-01-22 Completed Date: 2004-04-01 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 101154995 Medline TA: Org Biomol Chem Country: England |
Other Details:
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Languages: eng Pagination: 238-45 Citation Subset: IM |
Affiliation:
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C. P. 6128, Succ. Centre-ville, Montréal, Québec H3C 3J7, Canada. keillorj@chimie.umontreal.ca |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Binding Sites Binding, Competitive Enzyme Inhibitors / chemistry, metabolism, pharmacology Glutamic Acid / analogs & derivatives*, metabolism Glutathione / analogs & derivatives Kinetics Rats Stereoisomerism Sulfoxides / chemistry, metabolism, pharmacology gamma-Glutamyltransferase / antagonists & inhibitors, chemistry*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Sulfoxides; 56-86-0/Glutamic Acid; 70-18-8/Glutathione; EC 2.3.2.2/gamma-Glutamyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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