CDDO-imidazolide Targets Multiple Amino Acid Residues on the Nrf2 Adaptor, Keap1

Meng, Xiaoli ORCID: 0000-0002-7774-2075, Waddington, James C ORCID: 0000-0003-2641-5055, Tailor, Arun, Lister, Adam, Hamlett, Jane, Berry, Neil ORCID: 0000-0003-1928-0738, Park, B Kevin ORCID: 0000-0001-8384-824X and Sporn, Michael B
(2020) CDDO-imidazolide Targets Multiple Amino Acid Residues on the Nrf2 Adaptor, Keap1. JOURNAL OF MEDICINAL CHEMISTRY, 63 (17). pp. 9965-9976.

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Synthetic triterpenoids including CDDO, its methyl ester (CDDO-Me, bardoxolone methyl), and its imidazolide (CDDO-Im) enhance Nrf2-mediated antioxidant and anti-inflammatory activity in many diseases by reacting with thiols on the adaptor protein, Keap1. Unlike monofunctional CDDO-Me, the bifunctional analog, CDDO-Im, has a second reactive site (imidazolide) and can covalently bind to amino acids other than cysteine on target proteins such as glutathione S-transferase pi (GSTP), serum albumin, or Keap1. Here we show for the first time that bifunctional CDDO-Im (in contrast to CDDO-Me), as low as 50 nM, can covalently transacylate arginine and serine residues in GSTP and cross-link them to adjacent cysteine residues. Moreover, we show that CDDO-Im binds covalently to Keap1 by forming permanent Michael adducts with eight different cysteines, and acyl adducts with lysine and several tyrosine residues. Modeling studies suggest that the Tyr 85 adduct stabilizes the Keap1-Cul3 complex, thereby enhancing the potency of CDDO-Im.

Item Type: Article
Uncontrolled Keywords: Humans, Oleanolic Acid, Imidazoles, Cullin Proteins, Amino Acid Sequence, Glutathione S-Transferase pi, Protein Multimerization, Molecular Docking Simulation, Kelch-Like ECH-Associated Protein 1, Serum Albumin, Human
Depositing User: Symplectic Admin
Date Deposited: 02 Oct 2020 10:08
Last Modified: 18 Jan 2023 23:30
DOI: 10.1021/acs.jmedchem.0c01088
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