(-)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study.
Mar Drugs
; 16(7)2018 Jul 19.
Article
en En
| MEDLINE
| ID: mdl-30029468
ABSTRACT
Upon acylation of the proteasome by the ß-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-ß-lactonization strategy to construct the bicyclic ß-lactone core, enabled synthesis of (â»)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasomehomoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirroles
/
Complejo de la Endopetidasa Proteasomal
/
Inhibidores de Proteasoma
/
Lactonas
Idioma:
En
Revista:
Mar Drugs
Asunto de la revista:
BIOLOGIA
/
FARMACOLOGIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Alemania