Crystal Structures of Escherichia coli γ-Glutamyltranspeptidase in Complex with AZASERINE (cas 115-02-6) and Acivicin: Novel Mechanistic Implication for Inhibition by Glutamine Antagonists

Add time:08/26/2019    Source:sciencedirect.com

γ-Glutamyltranspeptidase (GGT) catalyzes the cleavage of such γ-glutamyl compounds as glutathione, and the transfer of their γ-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 (cas 115-02-6) 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 Å resolution. Both inhibitors are bound to GGT at its substrate-binding pocket in a manner similar to that observed previously with the γ-glutamyl-enzyme intermediate. They form a covalent bond with the Oγ atom of Thr391, the catalytic residue of GGT. Their α-carboxy and α-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 sp3-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.

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