Heparan-6-O-endosulfatase 2, a cancer-related proteoglycan enzyme, is effectively inhibited by a specific sea cucumber fucosylated glycosaminoglycan.
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| Format: | Artículo científico |
| Langue: | en |
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Glycobiology
2025
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| author | Farrag, Marwa Aljuhani, Reem Benicky, Julius Al Ahmed, Hoda Misra, Sandeep K Mishra, Sushil K Sharp, Joshua S Doerksen, Robert J Goldman, Radoslav Pomin, Vitor H |
| author_facet | Farrag, Marwa Aljuhani, Reem Benicky, Julius Al Ahmed, Hoda Misra, Sandeep K Mishra, Sushil K Sharp, Joshua S Doerksen, Robert J Goldman, Radoslav Pomin, Vitor H Farrag, Marwa Aljuhani, Reem Benicky, Julius Al Ahmed, Hoda Misra, Sandeep K Mishra, Sushil K Sharp, Joshua S Doerksen, Robert J Goldman, Radoslav Pomin, Vitor H |
| collection | PubMed - marine biology |
| contents | Heparan-6-O-endosulfatase 2, a cancer-related proteoglycan enzyme, is effectively inhibited by a specific sea cucumber fucosylated glycosaminoglycan. Farrag, Marwa Aljuhani, Reem Benicky, Julius Al Ahmed, Hoda Misra, Sandeep K Mishra, Sushil K Sharp, Joshua S Doerksen, Robert J Goldman, Radoslav Pomin, Vitor H Animals Sulfotransferases Humans Sea Cucumbers Chondroitin Sulfates Enzyme Inhibitors Holothuria Glycosaminoglycans Sulfatases Heparan-6-O-endosulfatase 2 (Sulf-2) is a proteoglycan enzyme that modifies sulfation of heparan sulfate proteoglycans. Dysregulation of Sulf-2 is associated with various pathological conditions, including cancer, which makes Sulf-2 a potential therapeutic target. Despite the key pathophysiological roles of Sulf-2, inhibitors remain insufficiently developed. In previous work, a fucosylated chondroitin sulfate from the sea cucumber Holothuria floridana (HfFucCS) exhibited potent Sulf-2 inhibition. This study investigates the structural basis of HfFucCS-mediated Sulf-2 inhibition, examines the binding profile of HfFucCS to Sulf-2, and explores the mode of inhibition. Additionally, a structurally diverse library of sulfated poly/oligosaccharides, including common glycosaminoglycans and unique marine sulfated glycans, was screened for Sulf-2 inhibition. Results from a high-throughput arylsulfatase assay and specific 6-O-desulfation assay have proved that HfFucCS is the most potent among the tested sulfated glycans, likely due to the presence of the unique 3,4-disulfated fucose structural motif. HfFucCS demonstrated non-competitive inhibition, and inhibitory analysis of its low-molecular-weight fragments suggests a minimum length of ~7.5 kDa for effective inhibition. Surface plasmon resonance analyses revealed that Sulf-2 binds to surface heparin with high affinity (KD of 0.817 nM). HfFucCS and its derivatives effectively disrupt this interaction. Results from mass spectrometry-hydroxyl radical protein footprinting and repulsive scaling replica exchange molecular dynamics indicate similarities in the binding of heparin and HfFucCS oligosaccharides to both the catalytic and hydrophilic domains of Sulf-2. These findings reveal the unique inhibitory properties of a structurally distinct marine glycosaminoglycan, supporting its further investigation as a selective and effective inhibitor for Sulf-2-associated cancer events. |
| format | Artículo científico |
| id | pubmed_40302034 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Glycobiology |
| record_format | pubmed |
| spellingShingle | Heparan-6-O-endosulfatase 2, a cancer-related proteoglycan enzyme, is effectively inhibited by a specific sea cucumber fucosylated glycosaminoglycan. Farrag, Marwa Aljuhani, Reem Benicky, Julius Al Ahmed, Hoda Misra, Sandeep K Mishra, Sushil K Sharp, Joshua S Doerksen, Robert J Goldman, Radoslav Pomin, Vitor H Animals Sulfotransferases Humans Sea Cucumbers Chondroitin Sulfates Enzyme Inhibitors Holothuria Glycosaminoglycans Sulfatases Heparan-6-O-endosulfatase 2, a cancer-related proteoglycan enzyme, is effectively inhibited by a specific sea cucumber fucosylated glycosaminoglycan. Farrag, Marwa Aljuhani, Reem Benicky, Julius Al Ahmed, Hoda Misra, Sandeep K Mishra, Sushil K Sharp, Joshua S Doerksen, Robert J Goldman, Radoslav Pomin, Vitor H Animals Sulfotransferases Humans Sea Cucumbers Chondroitin Sulfates Enzyme Inhibitors Holothuria Glycosaminoglycans Sulfatases Heparan-6-O-endosulfatase 2 (Sulf-2) is a proteoglycan enzyme that modifies sulfation of heparan sulfate proteoglycans. Dysregulation of Sulf-2 is associated with various pathological conditions, including cancer, which makes Sulf-2 a potential therapeutic target. Despite the key pathophysiological roles of Sulf-2, inhibitors remain insufficiently developed. In previous work, a fucosylated chondroitin sulfate from the sea cucumber Holothuria floridana (HfFucCS) exhibited potent Sulf-2 inhibition. This study investigates the structural basis of HfFucCS-mediated Sulf-2 inhibition, examines the binding profile of HfFucCS to Sulf-2, and explores the mode of inhibition. Additionally, a structurally diverse library of sulfated poly/oligosaccharides, including common glycosaminoglycans and unique marine sulfated glycans, was screened for Sulf-2 inhibition. Results from a high-throughput arylsulfatase assay and specific 6-O-desulfation assay have proved that HfFucCS is the most potent among the tested sulfated glycans, likely due to the presence of the unique 3,4-disulfated fucose structural motif. HfFucCS demonstrated non-competitive inhibition, and inhibitory analysis of its low-molecular-weight fragments suggests a minimum length of ~7.5 kDa for effective inhibition. Surface plasmon resonance analyses revealed that Sulf-2 binds to surface heparin with high affinity (KD of 0.817 nM). HfFucCS and its derivatives effectively disrupt this interaction. Results from mass spectrometry-hydroxyl radical protein footprinting and repulsive scaling replica exchange molecular dynamics indicate similarities in the binding of heparin and HfFucCS oligosaccharides to both the catalytic and hydrophilic domains of Sulf-2. These findings reveal the unique inhibitory properties of a structurally distinct marine glycosaminoglycan, supporting its further investigation as a selective and effective inhibitor for Sulf-2-associated cancer events. |
| title | Heparan-6-O-endosulfatase 2, a cancer-related proteoglycan enzyme, is effectively inhibited by a specific sea cucumber fucosylated glycosaminoglycan. |
| topic | Animals Sulfotransferases Humans Sea Cucumbers Chondroitin Sulfates Enzyme Inhibitors Holothuria Glycosaminoglycans Sulfatases |
| url | https://pubmed.ncbi.nlm.nih.gov/40302034/ |