Characterization of the modification of Kelch-like ECH-associated protein 1 by different fumarates.

Lingzhi Qu, Ming Guo, Huajun Zhang, Xiaojuan Chen, Hudie Wei, Longying Jiang, Jun Li, Zhuchu Chen, Shuyan Dai, Yongheng Chen

Biochemical and biophysical research communications 2022 May 21

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Fumarates (fumaric acid esters), primarily dimethyl fumarate (DMF) and monoethyl fumarate (MEF) and its salts, are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. It is widely believed that the pharmaceutical activities of fumarates are exerted through the Keap1-Nrf2 pathway. Although it has been revealed that DMF and MEF differentially modify specific Keap1 cysteine residues and result in the differential activation of Nrf2, how the modification of DMF and MEF impacts the biochemical properties of Keap1 has not been well characterized. Here, we found that both DMF and MEF can only modify the BTB domain of Keap1 and that only C151 is accessible for covalent binding in vitro. Dynamic fluorescence scanning (DSF) assays showed that the modification of DMF to Keap1 BTB increased its thermal stability, while the modification of MEF dramatically decreased its thermal stability. Further crystal structures revealed no significant conformational variation between the DMF-modified and MEF-modified BTBs. Overall, our biochemical and structural study provides a better understanding of the covalent modification of fumarates to Keap1 and may suggest fundamentally different mechanisms adopted by fumarates in regulating the Keap1-Nrf2 pathway. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Lingzhi Qu, Ming Guo, Huajun Zhang, Xiaojuan Chen, Hudie Wei, Longying Jiang, Jun Li, Zhuchu Chen, Shuyan Dai, Yongheng Chen. Characterization of the modification of Kelch-like ECH-associated protein 1 by different fumarates. Biochemical and biophysical research communications. 2022 May 21;605:9-15