Trisaccharide Sulfate and Its Sulfonamide as an Effective Substrate and Inhibitor of Human Endo‑O‑sulfatase‑1

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-sulfa...

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Published in:Journal of the American Chemical Society 2020-03, Vol.142 (11), p.5282-5292
Main Authors: Chiu, Li-Ting, Sabbavarapu, Narayana Murthy, Lin, Wei-Chen, Fan, Chiao-Yuan, Wu, Chih-Chung, Cheng, Ting-Jen Rachel, Wong, Chi-Huey, Hung, Shang-Cheng
Format: Article
Language:English
Subjects:
Enzyme Assays
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Heparitin Sulfate - chemistry
Humans
Kinetics
Substrate Specificity
Sulfatases - antagonists & inhibitors
Sulfatases - chemistry
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfotransferases - antagonists & inhibitors
Sulfotransferases - chemistry
Trisaccharides - chemical synthesis
Trisaccharides - chemistry
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Summary: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, K i = 0.36 μM, and K D = 12 nM.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.0c00005