Function of Conserved Residues of Human Glutathione Synthetase: Implications for the ATP-grasp Enzymes

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This article discusses human glutathione synthetase, an enzyme that belongs to the glutathione synthetase ATP-binding domain-like superfamily.

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Dinescu, Adriana; Cundari, Thomas R., 1964-; Bhansali, Vikas S.; Luo, Jia-Li & Anderson, Mary E. February 27, 2004.

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This article discusses human glutathione synthetase, an enzyme that belongs to the glutathione synthetase ATP-binding domain-like superfamily.

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Abstract: Glutathione synthetase is an enzyme that belongs to the glutathione synthetase ATP-binding domain-like superfamily. It catalyzes the second step in the biosynthesis of glutathione from y-glutamylcysteine and glycine in an ATP-dependent manner. Glutathione synthetase has been purified and sequenced from a variety of biological sources; still, its exact mechanism is not fully understood. A variety of structural alignment methods were applied and four highly conserved residues of human glutathione synthetase (Glu-144, Asn-146, Lys-305, and Lys-364) were identified in the binding site. The function of these was studied by experimental and computational site-directed mutagenesis. The three-dimensional coordinates for several human glutathione synthetase mutant enzymes were obtained using molecular mechanics and molecular dynamics simulation techniques, starting from the reported crystal structure of human glutathione synthetase. Consistent with circular dichroism spectroscopy, the authors' results showed no major changes to overall enzyme structure upon residue mutation. However, semiempirical calculations revealed that ligand binding is affected by these mutations. The key interactions between conserved residues and ligands were detected and found to be essential for enzymatic activity. Particularly, the negatively charged Glu-144 residue plays a major role in catalysis.

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  • Journal of Biological Chemistry, 2004, Rockville: American Society for Biochemistry and Molecular Biology, pp. 22412-22421

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  • Publication Title: Journal of Biological Chemistry
  • Volume: 279
  • Issue: 21
  • Page Start: 22412
  • Page End: 22421
  • Pages: 10
  • Peer Reviewed: Yes

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  • February 27, 2004

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  • Feb. 13, 2012, 2:23 p.m.

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  • April 2, 2014, 2:22 p.m.

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Dinescu, Adriana; Cundari, Thomas R., 1964-; Bhansali, Vikas S.; Luo, Jia-Li & Anderson, Mary E. Function of Conserved Residues of Human Glutathione Synthetase: Implications for the ATP-grasp Enzymes, article, February 27, 2004; [Rockville, Maryland]. (digital.library.unt.edu/ark:/67531/metadc75414/: accessed December 15, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.