Lherbet Christian, Keillor Jeffrey W
C. P. 6128, Succ. Centre-ville, Montréal, Québec H3C 3J7, Canada.
Org Biomol Chem. 2004 Jan 21;2(2):238-45. doi: 10.1039/b310767a. Epub 2003 Dec 2.
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.
γ-谷氨酰转肽酶（GGT）催化γ-谷氨酰基从供体底物转移至不同受体，如氨基酸和水。已知GGT对其供体底物的α-立体中心显示出相对较低的立体特异性。在本研究中，我们研究了其对L-谷氨酸不同类似物δ位立体中心的立体特异性。值得注意的是，L-蛋氨酸亚砜能被很好地识别，而L-蛋氨酸砜和L-蛋氨酸亚砜亚胺则不能。此外，当分离并测试L-蛋氨酸亚砜的合成γ-非对映异构体时，发现GGT在γ位显示出显著的立体特异性，以3.5 mM的抑制常数（K(i)）结合S(C)S(S)非对映异构体，而S(C)R(S)非对映异构体则不被识别。最后，使用亚砜作为GGT的新药理学基团，我们合成并测试了一种谷胱甘肽类似物，以获得一种非常有前景的竞争性抑制剂，其抑制常数（K(i)）为(53±3)μM。
