ASPARTATE 458 of Human Glutathione Synthetase is Important for Cooperativity and Active Site Structure

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Article discussing ASPARTATE 458 of human glutathione synthetase.

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17 p.: ill.

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Brown, Teresa R.; Drummond, Michael L.; Barelier, Sarah; Crutchfield, Amanda S.; Dinescu, Adriana; Slavens, Kerri D. et al. Creation Date: Unknown.

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Article discussing ASPARTATE 458 of human glutathione synthetase.

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17 p.: ill.

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This is the accepted manuscript version of the article. Reprinted with permission from Elsevier Science Ltd., all rights reserved. The final definitive version is available here: http://www.sciencedirect.com/science/article/pii/S0006291X1101179X

Abstract: Human glutathione synthetase (hGS) catalyzes the second ATP-dependent step in the biosynthesis of glutathione (GSH) and is negatively cooperative to the γ-glutamyl substrate. The hGS active site is composed of three highly conserved catalytic loops, notably the alanine rich A-loop. Experimental and computational investigations of the impact of mutation of Asp458 are reported, and thus the role of this A-loop residue on hGS structure, activity, negativity cooperativity and stability is defined. Several Asp458 hGS mutants (D458A, D458N, D458R) were constructed using site-directed mutagenesis and their activities determined (10, 15, and 7% of wild-type hGS, respectively). The Michaelis-Menten constant (Kм) was determined for all three substrates (glycine, GAB, ATP): glycine Kм increased by 30 - 115 fold, GAB Kм decreased by 8 - 17 fold, and the ATP Kм was unchanged. All Asp458 mutants display a change in cooperativity from negative cooperativity to non-cooperative. All mutants show similar stability as compared to wild-type hGS, as determined by differential scanning calorimetry. The findings indicate that Asp458 is essential for hGS catalysis and that it impacts the allostery of hGS.

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  • Biochemical and Biophysical Research Communications, 2011, Amsterdam: Elsevier Science Ltd., pp. 536-542

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  • Publication Title: Biochemical and Biophysical Research Communications
  • Volume: 411
  • Issue: 3
  • Page Start: 536
  • Page End: 542
  • Peer Reviewed: Yes

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  • August 5, 2011

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  • Sept. 13, 2013, 2:58 p.m.

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  • May 28, 2014, 2:32 p.m.

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Brown, Teresa R.; Drummond, Michael L.; Barelier, Sarah; Crutchfield, Amanda S.; Dinescu, Adriana; Slavens, Kerri D. et al. ASPARTATE 458 of Human Glutathione Synthetase is Important for Cooperativity and Active Site Structure, article, Date Unknown; [Amsterdam, Netherlands]. (digital.library.unt.edu/ark:/67531/metadc181678/: accessed October 22, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.