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Tunicate Heparan Sulfate Enriched in 2-Sulfated β-Glucuronic Acid: Structure, Anticoagulant Activity, and Inhibitory Effect on the Binding of Human Colon Adenocarcinoma Cells to Immobilized P-Selectin

1
Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, 21941-913 Rio de Janeiro, RJ, Brazil
2
Institute of Physiology, University of Zurich and Zurich Center for Integrative Human Physiology, 8057 Zurich, Switzerland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
In memory of Dr. Eliene O. Kozlowski who passed away.
Mar. Drugs 2019, 17(6), 351; https://doi.org/10.3390/md17060351
Received: 20 May 2019 / Revised: 1 June 2019 / Accepted: 5 June 2019 / Published: 12 June 2019
Heparin or highly sulfated heparan sulfate (HS) has been described in different invertebrates. In ascidians (Chordata-Tunicata), these glycosaminoglycans occur in intracellular granules of oocyte accessory cells and circulating basophil-like cells, resembling mammalian mast cells and basophils, respectively. HS is also a component of the basement membrane of different ascidian organs. We have analyzed an HS isolated from the internal organs of the ascidian Phallusia nigra, using solution 1H/13C NMR spectroscopy, which allowed us to identify and quantify the monosaccharides found in this glycosaminoglycan. A variety of α-glucosamine units with distinct degrees of sulfation and N-acetylation were revealed. The hexuronic acid units occur both as α-iduronic acid and β-glucuronic acid, with variable sulfation at the 2-position. A peculiar structural aspect of the tunicate HS is the high content of 2-sulfated β-glucuronic acid, which accounts for one-third of the total hexuronic acid units. Another distinct aspect of this HS is the occurrence of high content of N-acetylated α-glucosamine units bearing a sulfate group at position 6. The unique ascidian HS is a potent inhibitor of the binding of human colon adenocarcinoma cells to immobilized P-selectin, being 11-fold more potent than mammalian heparin, but almost ineffective as an anticoagulant. Thus, the components of the HS structure required to inhibit coagulation and binding of tumor cells to P-selectin are distinct. Our results also suggest that the regulation of the pathway involved in the biosynthesis of glycosaminoglycans suffered variations during the evolution of chordates. View Full-Text
Keywords: heparan sulfate; cancer; coagulation; ascidian glycosaminoglycans; P-selectin; marine biology; nuclear magnetic resonance heparan sulfate; cancer; coagulation; ascidian glycosaminoglycans; P-selectin; marine biology; nuclear magnetic resonance
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Abreu, W.S.; Soares, P.A.G.; Motta, J.M.; Kozlowski, E.O.; Teixeira, F.C.O.B.; Soares, M.A.; Borsig, L.; Mourão, P.A.S.; Pavão, M.S.G. Tunicate Heparan Sulfate Enriched in 2-Sulfated β-Glucuronic Acid: Structure, Anticoagulant Activity, and Inhibitory Effect on the Binding of Human Colon Adenocarcinoma Cells to Immobilized P-Selectin. Mar. Drugs 2019, 17, 351.

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