8e07

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Heparanase (HPSE) is the only mammalian endo-beta-glucuronidase known to catalyze the degradation of heparan sulfate. Dysfunction of HPSE activity has been linked to several disease states, resulting in HPSE becoming the target of numerous therapeutic programs, yet no drug has passed clinical trials to date. Pentosan polysulfate sodium (PPS) is a heterogeneous, FDA-approved drug for the treatment of interstitial cystitis and a known HPSE inhibitor. However, due to its heterogeneity, characterization of its mechanism of HPSE inhibition is challenging. Here, we show that inhibition of HPSE by PPS is complex, involving multiple overlapping binding events, each influenced by factors such as oligosaccharide length and inhibitor-induced changes in the protein secondary structure. The present work advances our molecular understanding of the inhibition of HPSE and will aid in the development of therapeutics for the treatment of a broad range of pathologies associated with enzyme dysfunction, including cancer, inflammatory disease, and viral infections.
Heparanase (HPSE) is the only mammalian endo-beta-glucuronidase known to catalyze the degradation of heparan sulfate. Dysfunction of HPSE activity has been linked to several disease states, resulting in HPSE becoming the target of numerous therapeutic programs, yet no drug has passed clinical trials to date. Pentosan polysulfate sodium (PPS) is a heterogeneous, FDA-approved drug for the treatment of interstitial cystitis and a known HPSE inhibitor. However, due to its heterogeneity, characterization of its mechanism of HPSE inhibition is challenging. Here, we show that inhibition of HPSE by PPS is complex, involving multiple overlapping binding events, each influenced by factors such as oligosaccharide length and inhibitor-induced changes in the protein secondary structure. The present work advances our molecular understanding of the inhibition of HPSE and will aid in the development of therapeutics for the treatment of a broad range of pathologies associated with enzyme dysfunction, including cancer, inflammatory disease, and viral infections.
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Complex Inhibitory Mechanism of Glycomimetics with Heparanase.,Whitefield C, Vo Y, Schwartz BD, Hepburn C, Ahmed FH, Onagi H, Banwell MG, Nelms K, Malins LR, Jackson CJ Biochemistry. 2023 Jun 27. doi: 10.1021/acs.biochem.3c00038. PMID:37368361<ref>PMID:37368361</ref>
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Complex Inhibitory Mechanism of Glycomimetics with Heparanase.,Whitefield C, Vo Y, Schwartz BD, Hepburn C, Ahmed FH, Onagi H, Banwell MG, Nelms K, Malins LR, Jackson CJ Biochemistry. 2023 Jul 18;62(14):2202-2215. doi: 10.1021/acs.biochem.3c00038. , Epub 2023 Jun 27. PMID:37368361<ref>PMID:37368361</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Current revision

Crystal structure of HPSE P6 in complex with triose pentosan inhibitor

PDB ID 8e07

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