Covalent Targeting of Glutamate Cysteine Ligase to Inhibit Glutathione Synthesis.
GCL
activity-based protein profiling
chemoproteomics
glutamate-cysteine ligase
glutathione
Journal
Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
revised:
24
09
2023
received:
18
05
2023
medline:
4
12
2023
pubmed:
27
9
2023
entrez:
27
9
2023
Statut:
ppublish
Résumé
Dysregulated oxidative stress plays a major role in cancer pathogenesis and some types of cancer cells are particularly vulnerable to inhibition of their cellular antioxidant capacity. Glutamate-cysteine ligase (GCL) is the first and rate-limiting step in the synthesis of the major cellular antioxidant glutathione (GSH). Developing a GCL inhibitor may be an attractive therapeutic strategy for certain cancer types that are particularly sensitive to oxidative stress. In this study, we reveal a cysteine-reactive ligand, EN25, that covalently targets an allosteric cysteine C114 on GCLM, the modifier subunit of GCL, and leads to inhibition of GCL activity. This interaction also leads to reduced cellular GSH levels and impaired cell viability in ARID1A-deficient cancer cells, which are particularly vulnerable to glutathione depletion, but not in ARID1A-positive cancer cells. Our studies uncover a novel potential ligandable site within GCLM that can be targeted to inhibit GSH synthesis in vulnerable cancer cell types.
Identifiants
pubmed: 37756477
doi: 10.1002/cbic.202300371
doi:
Substances chimiques
Glutamate-Cysteine Ligase
EC 6.3.2.2
Antioxidants
0
Cysteine
K848JZ4886
Enzyme Inhibitors
0
Glutathione
GAN16C9B8O
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202300371Subventions
Organisme : Mark Foundation for Cancer Research ASPIRE Award
Informations de copyright
© 2023 Wiley-VCH GmbH.
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