{sup 1}H NMR spectroscopic studies establish that heparanase is a retaining glycosidase
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072 (Australia)
- Institute for Glycomics, Griffith University Gold Coast Campus, QLD 4222 (Australia)
Highlights: •{sup 1}H and {sup 13}C NMR chemical shifts of fondaparinux were fully assigned by 1D and 2D NMR techniques. •Hydrolysis of fondaparinux by heparanase was monitored by {sup 1}H NMR spectroscopy. •Heparanase is established to be a retaining glycosidase. -- Abstract: Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains of proteoglycans in basement membranes and the extracellular matrix (ECM). Heparanase is implicated in several diverse pathological processes associated with ECM degradation such as metastasis, inflammation and angiogenesis and is thus an important target for anti-cancer and anti-inflammatory drug discovery. Heparanase has been classed as belonging to the clan A glycoside hydrolase family 79 based on sequence analysis, secondary structure predictions and mutagenic analysis, and thus it has been inferred that it is a retaining glycosidase. However, there has been no direct experimental evidence to support this conclusion. Herein we describe {sup 1}H NMR spectroscopic studies of the hydrolysis of the pentasaccharide substrate fondaparinux by heparanase, and provide conclusive evidence that heparanase hydrolyses its substrate with retention of configuration and is thus established as a retaining glycosidase. Knowledge of the mechanism of hydrolysis may have implications for future design of inhibitors for this important drug target.
- OSTI ID:
- 22242244
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 443; ISSN BBRCA9; ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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