Article

Probing the stereochemistry of the active site of gamma-glutamyl transpeptidase using sulfur derivatives of l-glutamic acid.

C. P. 6128, Succ. Centre-ville, Montréal, Québec H3C 3J7, Canada.
Organic & Biomolecular Chemistry (impact factor: 3.7). 02/2004; 2(2):238-45. DOI:10.1039/b310767a pp.238-45
Source: PubMed

ABSTRACT 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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Keywords

alpha-stereocentre
 
amino acids
 
analogue
 
delta-position
 
different acceptors
 
different analogues
 
donor substrate
 
donor substrates
 
gamma-glutamyl moiety
 
Gamma-glutamyl transpeptidase
 
gamma-position
 
GGT
 
glutathione
 
L-methionine sulfoximine
 
new pharmacophore
 
promising competitive inhibitor