Ebselen: Mechanisms of Glutamate Dehydrogenase and Glutaminase Enzyme Inhibition

ACS Chemical Biology
Yan YuBenfang Helen Ruan

Abstract

Ebselen modulates target proteins through redox reactions with selenocysteine/cysteine residues, or through binding to the zinc finger domains. However, a recent contradiction in ebselen inhibition of kidney type glutaminase (KGA) stimulated our interest in investigating its inhibition mechanism with glutamate dehydrogenase (GDH), KGA, thioredoxin reductase (TrxR), and glutathione S-transferase. Fluorescein- or biotin-labeled ebselen derivatives were synthesized for mechanistic analyses. Biomolecular interaction analyses showed that only GDH, KGA, and TrxR proteins can bind to the ebselen derivative, and the binding to GDH and KGA could be competed off by glutamine or glutamate. From the gel shift assays, the fluorescein-labeled ebselen derivative could co-migrate with hexameric GDH and monomeric/dimeric TrxR in a dose-dependent manner; it also co-migrated with KGA but disrupted the tetrameric form of the KGA enzyme at a high compound concentration. Further proteomic analysis demonstrated that the ebselen derivative could cross-link with proteins through a specific cysteine at the active site of GDH and TrxR proteins, but for KGA protein, the binding site is at the N-terminal appendix domain outside of the catalytic domain, whi...Continue Reading

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Citations

Feb 23, 2018·Assay and Drug Development Technologies·Yanhong JinBenfang Helen Ruan
Aug 10, 2018·Chemical Communications : Chem Comm·Zhenzhen ChenBo Tang
Oct 12, 2018·Metallomics : Integrated Biometal Science·C Abbehausen
Mar 19, 2021·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Manoela SacramentoDiego Alves
Dec 26, 2018·Biochemical and Biophysical Research Communications·Wei HouBenfang Helen Ruan
Apr 2, 2021·Archives of Toxicology·Cristina W NogueiraJoão B T Rocha
Jul 6, 2019·European Journal of Medicinal Chemistry·Florence LerouxRebecca Deprez-Poulain
Jul 25, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Claudio SantiLuca Sancineto
Dec 7, 2021·Organic & Biomolecular Chemistry·Shengsheng LinZhixiong Ruan

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