Molecular Basis for Inhibition of Heparanases and ß-Glucuronidases by Siastatin B.
J Am Chem Soc
; 146(1): 125-133, 2024 01 10.
Article
en En
| MEDLINE
| ID: mdl-38118176
ABSTRACT
Siastatin B is a potent and effective iminosugar inhibitor of three diverse glycosidase classes, namely, sialidases, ß-d-glucuronidases, and N-acetyl-glucosaminidases. The mode of inhibition of glucuronidases, in contrast to sialidases, has long been enigmatic as siastatin B appears too bulky and incorrectly substituted to be accommodated within a ß-d-glucuronidase active site pocket. Herein, we show through crystallographic analysis of protein-inhibitor complexes that siastatin B generates both a hemiaminal and a 3-geminal diol iminosugar (3-GDI) that are, rather than the parent compound, directly responsible for enzyme inhibition. The hemiaminal product is the first observation of a natural product that belongs to the noeuromycin class of inhibitors. Additionally, the 3-GDI represents a new and potent class of the iminosugar glycosidase inhibitor. To substantiate our findings, we synthesized both the gluco- and galacto-configured 3-GDIs and characterized their binding both structurally and kinetically to exo-ß-d-glucuronidases and the anticancer target human heparanase. This revealed submicromolar inhibition of exo-ß-d-glucuronidases and an unprecedented binding mode by this new class of inhibitor. Our results reveal the mechanism by which siastatin B acts as a broad-spectrum glycosidase inhibitor, identify a new class of glycosidase inhibitor, and suggest new functionalities that can be incorporated into future generations of glycosidase inhibitors.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Inhibidores Enzimáticos
/
Glucuronidasa
Límite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Año:
2024
Tipo del documento:
Article
País de afiliación:
Países Bajos