Anderson, MaryIngle, BrandallShrestha, BiseshDe Jesus, MargaritaConrad-Webb, HeatherCundari, Thomas2019-01-182019-01-182018This is the publisher’s version of an article that is available at https://doi.org/10.1016/j.csbj.2018.11.008. Recommended citation: Ingle, B. L., Shrestha, B., De Jesus, M. C., Conrad-Webb, H. M., Anderson, M. E., & Cundari, T. R. (2019). Genetic mutations in the S-loop of human glutathione synthetase: Links between substrate binding, active site structure and allostery. Computational and Structural Biotechnology Journal, 17, 31–38. This item has been deposited in accordance with publisher copyright and licensing terms and with the author’s permission.https://hdl.handle.net/11274/10894https://doi.org/10.1016/j.csbj.2018.11.008The second step in the biosynthesis of the cellular antioxidant glutathione (GSH) is catalyzed by human glutathione synthetase (hGS), a negatively cooperative homodimer. Patients with mutations in hGS have been reported to exhibit a range of symptoms from hemolytic anemia and metabolic acidosis to neurological disorders and premature death. Several patient mutations occur in the S-loop of hGS, a series of residues near the negatively cooperative γ-GC substrate binding site. Experimental point mutations and molecular dynamic simulations show the S-loop not only binds γ-GC through a salt bridge and multiple hydrogen bonds, but the residues also modulate allosteric communication in hGS. By elucidating the role of S-loop residues in active site structure, substrate binding, and allostery, the atomic level sequence of events that leads to the detrimental effects of hGS mutations in patients are more fully understood.BiosynthesisGlutathioneGlutathione synthetasePoint mutationsMolecular dynamic simulationsHydrogen bondsActive siteAllosteryArticleCC BY-NC-ND