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首页> 外文期刊>Journal of Molecular Biology >Crystal structures of Escherichia coli gamma-glutamyltranspeptidase in complex with azaserine and acivicin: novel mechanistic implication for inhibition by glutamine antagonists.
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Crystal structures of Escherichia coli gamma-glutamyltranspeptidase in complex with azaserine and acivicin: novel mechanistic implication for inhibition by glutamine antagonists.

机译：大肠杆菌gaz-谷氨酰转肽酶与azaserine和acivicin的晶体结构：谷氨酰胺拮抗剂抑制的新机制。

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摘要

gamma-Glutamyltranspeptidase (GGT) catalyzes the cleavage of such gamma-glutamyl compounds as glutathione, and the transfer of their gamma-glutamyl group to water or to other amino acids and peptides. GGT is involved in a number of biological phenomena such as drug resistance and metastasis of cancer cells by detoxification of xenobiotics. Azaserine and acivicin are classical and irreversible inhibitors of GGT, but their binding sites and the inhibition mechanisms remain to be defined. We have determined the crystal structures of GGT from Escherichia coli in complex with azaserine and acivicin at 1.65 A resolution. Both inhibitors are bound to GGT at its substrate-binding pocket in a manner similar to that observed previously with the gamma-glutamyl-enzyme intermediate. They form a covalent bond with the O(gamma) atom of Thr391, the catalytic residue of GGT. Their alpha-carboxy and alpha-amino groups are recognized by extensive hydrogen bonding and charge interactions with the residues that are conserved among GGT orthologs. The two amido nitrogen atoms of Gly483 and Gly484, which form the oxyanion hole, interact with the inhibitors directly or via a water molecule. Notably, in the azaserine complex the carbon atom that forms a covalent bond with Thr391 is sp(3)-hybridized, suggesting that the carbonyl of azaserine is attacked by Thr391 to form a tetrahedral intermediate, which is stabilized by the oxyanion hole. Furthermore, when acivicin is bound to GGT, a migration of the single and double bonds occurs in its dihydroisoxazole ring. The structural characteristics presented here imply that the unprecedented binding modes of azaserine and acivicin are conserved in all GGTs from bacteria to mammals and give a new insight into the inhibition mechanism of glutamine amidotransferases by these glutamine antagonists.
机译：γ-谷氨酰转肽酶（GGT）催化诸如谷胱甘肽的γ-谷氨酰基化合物的裂解，以及它们的γ-谷氨酰基向水或其它氨基酸和肽的转移。 GGT涉及许多生物现象，例如耐药性和异源生物排毒引起的癌细胞转移。 Azaserine和Acivicin是经典且不可逆的GGT抑制剂，但它们的结合位点和抑制机制仍有待确定。我们已经确定了来自大肠杆菌的GGT的晶体结构与azaserine和acivicin的复杂度为1.65A。两种抑制剂都以与先前用γ-谷氨酰胺酶中间体观察到的相似方式在其底物结合口袋处结合到GGT。它们与Thr391（GGT的催化残基）的O（γ）原子形成共价键。它们的α-羧基和α-氨基基团通过广泛的氢键结合以及与GGT直系同源物中保守的残基的电荷相互作用而被识别。形成氧阴离子孔的Gly483和Gly484的两个酰胺基氮原子直接或通过水分子与抑制剂相互作用。值得注意的是，在叠氮嗪络合物中，与Thr391形成共价键的碳原子被sp（3）杂化，这表明叠氮嗪的羰基受到Thr391的攻击而形成四面体中间体，该中间体被氧阴离子孔稳定。此外，当阿西维林与GGT结合时，单键和双键的迁移发生在其二氢异恶唑环中。这里呈现的结构特征暗示，从细菌到哺乳动物的所有GGT中，氮杂双胍和阿西维汀的前所未有的结合模式均得以保留，并为这些谷氨酰胺拮抗剂对谷氨酰胺酰胺转移酶的抑制机制提供了新的认识。

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