ArticleThe Journal of biological chemistry2010
Structural basis for feedback and pharmacological inhibition of Saccharomyces cerevisiae glutamate cysteine ligase.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
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- Characterization of a glutamate-cysteine ligase in Bombyx mori.Molecular biology reports · 2023Article
- Structures of prokaryotic ubiquitin-like protein Pup in complex with depupylase Dop reveal the mechanism of catalytic phosphate formation.Nature communications · 2021Article
- Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance.Antioxidants (Basel, Switzerland) · 2020Article
- Plant glutathione biosynthesis revisited: redox-mediated activation of glutamylcysteine ligase does not require homo-dimerization.The Biochemical journal · 2019Article
- Depupylase Dop Requires Inorganic Phosphate in the Active Site for Catalysis.The Journal of biological chemistry · 2017Article
- Biochemical and biophysical characterization ofBiochemistry and biophysics reports · 2016Article
- Phospholipid methylation controls Atg32-mediated mitophagy and Atg8 recycling.The EMBO journal · 2015Article
- Expression of bacterial GshF in Pichia pastoris for glutathione production.Applied and environmental microbiology · 2012Article
- Molecular modeling of Trypanosoma cruzi glutamate cysteine ligase and investigation of its interactions with glutathione.Journal of molecular modeling · 2012Article
- Glutathione degradation is a key determinant of glutathione homeostasis.The Journal of biological chemistry · 2012Article
- Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits.Biochemistry · 2011Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Structural characterization of glutamate cysteine ligase (GCL), the enzyme that catalyzes the initial, rate-limiting step in glutathione biosynthesis, has revealed many of the molecular details of substrate recognition. To further delineate the mechanistic details of this critical enzyme, we have determined the structures of two inhibited forms of Saccharomyces cerevisiae GCL (ScGCL), which shares significant sequence identity with the human enzyme. In vivo, GCL activity is feedback regulated by glutathione. Examination of the structure of ScGCL-glutathione complex (2.5 A; R = 19.9%, R(free) = 25.1%) indicates that the inhibitor occupies both the glutamate- and the presumed cysteine-binding site and disrupts the previously observed Mg(2+) coordination in the ATP-binding site. l-Buthionine-S-sulfoximine (BSO) is a mechanism-based inhibitor of GCL and has been used extensively to deplete glutathione in cell culture and in vivo model systems. Inspection of the ScGCL-BSO structure (2.2 A; R = 18.1%, R(free) = 23.9%) confirms that BSO is phosphorylated on the sulfoximine nitrogen to generate the inhibitory species and reveals contacts that likely contribute to transition state stabilization. Overall, these structures advance our understanding of the molecular regulation of this critical enzyme and provide additional details of the catalytic mechanism of the enzyme.
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