CDDO-imidazolide Targets Multiple Amino Acid Residues on the Nrf2 Adaptor, Keap1.
J Med Chem
; 63(17): 9965-9976, 2020 09 10.
Article
en En
| MEDLINE
| ID: mdl-32787104
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ácido Oleanólico
/
Proteína 1 Asociada A ECH Tipo Kelch
/
Imidazoles
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido