Trisaccharide Sulfate and Its Sulfonamide as an Effective Substrate and Inhibitor of Human Endo-O-sulfatase-1.
J Am Chem Soc
; 142(11): 5282-5292, 2020 03 18.
Article
em En
| MEDLINE
| ID: mdl-32083852
ABSTRACT
Human endo-O-sulfatases (Sulf-1 and Sulf-2) are extracellular heparan sulfate proteoglycan (HSPG)-specific 6-O-endosulfatases, which regulate a multitude of cell-signaling events through heparan sulfate (HS)-protein interactions and are associated with the onset of osteoarthritis. These endo-O-sulfatases are transported onto the cell surface to liberate the 6-sulfate groups from the internal d-glucosamine residues in the highly sulfated subdomains of HSPGs. In this study, a variety of HS oligosaccharides with different chain lengths and N- and O-sulfation patterns via chemical synthesis were systematically studied about the substrate specificity of human Sulf-1 employing the fluorogenic substrate 4-methylumbelliferyl sulfate (4-MUS) in a competition assay. The trisaccharide sulfate IdoA2S-GlcNS6S-IdoA2S was found to be the minimal-size substrate for Sulf-1, and substitution of the sulfate group at the 6-O position of the d-glucosamine unit with the sulfonamide motif effectively inhibited the Sulf-1 activity with IC50 = 0.53 µM, Ki = 0.36 µM, and KD = 12 nM.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfatases
/
Sulfonamidas
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Trissacarídeos
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Sulfotransferases
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Inibidores Enzimáticos
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article