Highly sulfated dermatan sulfates from ascidians -: Structure versus anticoagulant activity of these glycosaminoglycans

被引:144
作者
Pavao, MSG
Aiello, KRM
Werneck, CC
Silva, LCF
Valente, AP
Mulloy, B
Colwell, NS
Tollefsen, DM
Mourao, PAS
机构
[1] Univ Fed Rio de Janeiro, Ctr Ciencias Saude, Dept Bioquim Med, BR-21941590 Rio De Janeiro, Brazil
[2] Univ Hosp, Lab Tecido Conjunt, BR-21941590 Rio De Janeiro, Brazil
[3] Univ Fed Rio de Janeiro, Dept Bioquim Med, Ctr Nacl Ressonancia Magnet Nucl Macromol, BR-21941590 Rio De Janeiro, Brazil
[4] Natl Inst Biol Stand & Controls, Potters Bar EN6 3QG, Herts, England
[5] Washington Univ, Sch Med, Dept Internal Med, Div Hematol, St Louis, MO 63110 USA
关键词
D O I
10.1074/jbc.273.43.27848
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Dermatan sulfates with the same backbone structure [4-alpha-L-IdceA-1-->3-beta-D-GalNAc-1](n) but with different patterns of sulfation substitutions have been isolated from the ascidian body. All the ascidian dermatan sulfates have a high content of 2-O-sulfated alpha-L-iduronic acid residues but differ in the pattern of sulfation of the N-acetyl-beta-D-galactosamine units. Styela plicata and Halocynthia pyriformis have 4-O-sulfated units, but in Ascidian nigra they are 6-O-sulfated. This collection of ascidian dermatan sulfates (together with native and oversulfated mammalian dermatan sulfate), where the extent and position of sulfate substitution have been fully characterized, were tested in anticoagulant assays. Dermatan sulfate from A. nigra has no discernible anticoagulant activity, which indicates that 4-O-sulfation of the N-acetyl-beta-D-galactosamine is essential for the anticoagulant activity of this glycosaminoglycan, In contrast dermatan sulfates from S. plicata and H. pyriformis are potent anticoagulants due to potentiation of thrombin inhibition by heparin cofactor II. These ascidian dermatan sulfates have similar to 10-fold and similar to 6-fold higher activity with heparin cofactor II than native and an oversulfated mammalian dermatan sulfate, respectively. They have no effect on thrombin or factor Xa inhibition by antithrombin. These naturally oversulfated ascidian dermatan sulfates are sulfated at selected sites required for interaction with heparin cofactor II and thus have specific and potent anticoagulant activity.
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页码:27848 / 27857
页数:10
相关论文
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