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- W2060359803 abstract "In most organisms, glutathione (GSH) is synthesized by the sequential action of distinct enzymes, γ-glutamylcysteine synthetase (γ-GCS) and GSH synthetase (GS). In Streptococcus agalactiae, GSH synthesis is catalyzed by a single enzyme, γ-glutamylcysteine synthetase−glutathione synthetase (γ-GCS-GS). The N-terminal sequence of γ-GCS-GS is similar to Escherichia coli γ-GCS, but the C-terminal sequence is an ATP-grasp domain more similar to d-Ala, d-Ala ligase than to any known GS. In the present studies, C-terminally and N-terminally truncated constructs were characterized in order to define the limits of the γ-GCS and GS domains, respectively. Although WT γ-GCS-GS is nearly uninhibited by GSH (Ki ∼ 140 mM), shorter γ-GCS domain constructs were unexpectedly found to be strongly inhibited (Ki ∼ 15 mM), reproducing a physiologically important regulation seen in monofunctional γ-GCS enzymes. Because studies with E. coli γ-GCS implicate a flexible loop region in GSH binding, chimeras of S. agalactiae γ-GCS-GS were made containing γ-GCS domain flexible loop sequences from Enterococcus faecalis and Pasteurella multocida γ-GCS-GS, isoforms that are inhibited by GSH. Inhibition remained S. agalactiae-like (i.e., very weak). C-Terminal constructs of γ-GCS-GS have GS activity (0.01−0.04% of WT), but proper folding and significant GS activity required a covalently linked γ-GCS domain. In addition, site-directed mutants in the middle region of the γ-GCS-GS sequence established that GS activity depends on residues in a region that is also part of the γ-GCS domain. Our results provide new insights into the structure of γ-GCS-GS and suggest γ-GCS-GS evolved from a monomeric γ-GCS that became C-terminally fused to a multimeric ATP-grasp protein." @default.
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- W2060359803 date "2006-08-11" @default.
- W2060359803 modified "2023-09-23" @default.
- W2060359803 title "γ-Glutamylcysteine Synthetase−Glutathione Synthetase: Domain Structure and Identification of Residues Important in Substrate and Glutathione Binding" @default.
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- W2060359803 doi "https://doi.org/10.1021/bi052483v" @default.
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