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1.
We report for the first time that marine angiosperms (seagrasses) possess sulfated polysaccharides, which are absent in terrestrial and freshwater plants. The structure of the sulfated polysaccharide from the seagrass Ruppia maritima was determined. It is a sulfated D-galactan composed of the following regular tetrasaccharide repeating unit: [3-beta-D-Gal-2(OSO3)-1-->4-alpha-D-Gal-1-->4-alpha-D-Gal-1-->3-beta-D-Gal-4(OSO3)-1-->]. Sulfated galactans have been described previously in red algae and in marine invertebrates (ascidians and sea urchins). The sulfated galactan from the marine angiosperm has an intermediate structure when compared with the polysaccharides from these two other groups of organisms. Like marine invertebrate galactan, it expresses a regular repeating unit with a homogenous sulfation pattern. However, seagrass galactan contains the D-enantiomer of galactose instead of the L-isomer found in marine invertebrates. Like red algae, the marine angiosperm polysaccharide contains both alpha and beta units of D-galactose; however, these units are not distributed in an alternating order, as in algal galactan. Sulfated galactan is localized in the plant cell walls, mostly in rhizomes and roots, indicative of a relationship with the absorption of nutrients and of a possible structural function. The occurrence of sulfated galactans in marine organisms may be the result of physiological adaptations, which are not correlated with phylogenetic proximity. We suggest that convergent adaptation, due to environment pressure, may explain the occurrence of sulfated galactans in many marine organisms. 相似文献
2.
Marine alga is an abundant source of sulfated polysaccharides with potent anticoagulant activity. However, several attempts to identify the specific structural features in these compounds, which confer the biological activity, failed due to their complex, heterogeneous structure. We isolated and characterized several sulfated alpha-L-galactans and sulfated alpha-L-fucans from marine invertebrates. In contrast to the algal fucans and galactans, these invertebrate polysaccharides have a simple structure, composed of well-defined units of oligosaccharides. We employed two of these compounds to elucidate their structure-anticoagulant action relationship. Our results indicate that a 2-sulfated, 3-linked alpha-L-galactan, but not an alpha-L-fucan, is a potent thrombin inhibitor mediated by antithrombin or heparin cofactor II. The difference between the activities of these two polysaccharides is not very pronounced when factor Xa replaces thrombin. Thus, the anticoagulant activity of sulfated galactan and sulfated fucan is not merely a consequence of their charge density. The interaction of these polysaccharides with coagulation cofactors and their target proteases are specific. Identification of specific structural requirements in sulfated galactans and sulfated fucans necessary for interaction with coagulation cofactors is an essential step for a more rational approach to develop new anticoagulant and antithrombotic drugs. 相似文献
3.
Sulfated fucans are among the most widely studied of all the sulfated polysaccharides of non-mammalian origin that exhibit biological activities in mammalian systems. Examples of these polysaccharides extracted from echinoderms have simple structures, composed of oligosaccharide repeating units within which the residues differ by specific patterns of sulfation among different species. In contrast the algal fucans may have some regular repeating structure but are clearly more heterogeneous when compared with the echinoderm fucans. The structures of the sulfated fucans from brown algae also vary from species to species. We compared the anticoagulant activity of the regular and repetitive fucans from echinoderms with that of the more heterogeneous fucans from three species of brown algae. Our results indicate that different structural features determine not only the anticoagulant potency of the sulfated fucans but also the mechanism by which they exert this activity. Thus, the branched fucans from brown algae are direct inhibitors of thrombin, whereas the linear fucans from echinoderms require the presence of antithrombin or heparin cofactor II for inhibition of thrombin, as reported for mammalian glycosaminoglycans. The linear sulfated fucans from echinoderms have an anticoagulant action resembling that of mammalian dermatan sulfate and a modest action through antithrombin. A single difference of one sulfate ester per tetrasaccharide repeating unit modifies the anticoagulant activity of the polysaccharide markedly. Possibly the spatial arrangements of sulfate esters in the repeating tetrasaccharide unit of the echinoderm fucan mimics the site in dermatan sulfate with high affinity for heparin cofactor II. 相似文献
4.
Structure, biology, evolution, and medical importance of sulfated fucans and galactans 总被引:2,自引:0,他引:2
Sulfated fucans and galactans are strongly anionic polysaccharides found in marine organisms. Their structures vary among species, but their major features are conserved among phyla. Sulfated fucans are found in marine brown algae and echinoderms, whereas sulfated galactans occur in red and green algae, marine angiosperms, tunicates (ascidians), and sea urchins. Polysaccharides with 3-linked, beta-galactose units are highly conserved in some taxonomic groups of marine organisms and show a strong tendency toward 4-sulfation in algae and marine angiosperms, and 2-sulfation in invertebrates. Marine algae mainly express sulfated polysaccharides with complex, heterogeneous structures, whereas marine invertebrates synthesize sulfated fucans and sulfated galactans with regular repetitive structures. These polysaccharides are structural components of the extracellular matrix. Sulfated fucans and galactans are involved in sea urchin fertilization acting as species-specific inducers of the sperm acrosome reaction. Because of this function the structural evolution of sulfated fucans could be a component in the speciation process. The algal and invertebrate polysaccharides are also potent anticoagulant agents of mammalian blood and represent a potential source of compounds for antithrombotic therapies. 相似文献
5.
We investigated the mechanisms of anticoagulant activity mediated by sulfated galactans. The anticoagulant activity of sulfated polysaccharides is achieved mainly through potentiation of plasma cofactors, which are the natural inhibitors of coagulation proteases. Our results indicated the following. 1) Structural requirements for the interaction of sulfated galactans with coagulation inhibitors and their target proteases are not merely a consequence of their charge density. 2) The structural basis of this interaction is complex because it involves naturally heterogeneous polysaccharides but depends on the distribution of sulfate groups and on monosaccharide composition. 3) Sulfated galactans require significantly longer chains than heparin to achieve anticoagulant activity. 4) Possibly, it is the bulk structure of the sulfated galactan, and not a specific minor component as in heparin, that determines its interaction with antithrombin. 5) Sulfated galactans of approximately 15 to approximately 45 kDa bind to antithrombin but are unable to link the plasma inhibitor and thrombin. This last effect requires a molecular size above 45 kDa. 6) Sulfated galactan and heparin bind to different sites on antithrombin. 7) Sulfated galactans are less effective than heparin at promoting antithrombin conformational activation. Overall, these observations indicate that a different mechanism predominates over the conformational activation of antithrombin in ensuring the antithrombin-mediated anticoagulant activity of the sulfated galactans. Possibly, sulfated galactan connects antithrombin and thrombin, holding the protease in an inactive form. The conformational activation of antithrombin and the consequent formation of a covalent complex with thrombin appear to be less important for the anticoagulant activity of sulfated galactan than for heparin. Our results demonstrate that the paradigm of heparin-antithrombin interaction cannot be extended to other sulfated polysaccharides. Each type of polysaccharide may form a particular complex with the plasma inhibitor and the target protease. 相似文献
6.
Is there a correlation between structure and anticoagulant action of sulfated galactans and sulfated fucans? 总被引:5,自引:0,他引:5
We attempted to identify the specific structural features in sulfated galactans and sulfated fucans that confer anticoagulant activity. For this study we employed a variety of invertebrate polysaccharides with simple structures composed of well-defined units of oligosaccharides. Our results indicate that a 2-O-sulfated, 3-linked alpha-L-galactan, but not a alpha-L-fucan with a similar molecular size, is a potent thrombin inhibitor mediated by antithrombin or heparin cofactor II. The difference between the activities of these two polysaccharides is not very pronounced when factor Xa replaced thrombin. The occurrence of 2,4-di-O-sulfated units is an amplifying motif for 3-linked alpha-fucan-enhanced thrombin inhibition by antithrombin. If we replace antithrombin by heparin cofactor II, then the major structural requirement for the activity becomes single 4-O-sulfated fucose units. The presence of 2-O-sulfated fucose residues always had a deleterious effect on anticoagulant activity. Overall, our results indicate that the structural requirements for interaction of sulfated galactans and sulfated fucans with coagulation cofactors and their target proteases are stereospecific and not merely a consequence of their charge density and sulfate content. 相似文献
7.
《Process Biochemistry》2014,49(8):1352-1361
In this study, we isolated two fucosylated polysaccharide sulfates (ACP and HOP) from sea cucumber Acaudina molpadioidea and Holothuria nobilis, with an average molecular weight of 90.8 and 135.8 kDa, respectively. We investigated and compared their anticoagulant activities through anticoagulant assay. Our data showed that both polysaccharides possessed good anticoagulant activity, but HOP's activity was higher than that of ACP. Due to the different anticoagulant activities of ACP and HOP, we compared the preliminary structural characterizations of these two sulfated polysaccharides, and found that both ACP and HOP consisted of β-d-glucuronic acid, β-d-N-acetyl-galactosamine, α-l-fucose and sulfate groups. ACP and HOP had almost identical ratios of glucuronic acid, N-acetyl-galactosamine and fucose. However, the sulfate contents and sulfation patterns of fucose residues of ACP and HOP were obviously different. There were 4-O-sulfated fucose, 3,4-O-disulfated fucose and 2,4-O-disulfated fucose in ACP, but only 3-O-sulfated fucose and 2,4-O-disulfated fucose were present in HOP. Therefore, their distinct anticoagulant activities might be due to the different sulfate contents and sulfation patterns of their fucose residues. 相似文献
8.
A linear sulfated fucan with a regular repeating sequence of [3)-alpha-L-Fucp-(2SO4)-(1-->3)-alpha-L-Fucp-(4SO4)-(1-->3)-alpha-L-Fucp-(2,4SO4)-(1-->3)-alpha-L-Fucp-(2SO4)-(1-->]n is an anticoagulant polysaccharide mainly due to thrombin inhibition mediated by heparin cofactor II. No specific enzymatic or chemical method is available for the preparation of tailored oligosaccharides from sulfated fucans. We employ an apparently nonspecific approach to cleave this polysaccharide based on mild hydrolysis with acid. Surprisingly, the linear sulfated fucan was cleaved by mild acid hydrolysis on an ordered sequence. Initially a 2-sulfate ester of the first fucose unit is selectively removed. Thereafter the glycosidic linkage between the nonsulfated fucose residue and the subsequent 4-sulfated residue is preferentially cleaved by acid hydrolysis, forming oligosaccharides with well-defined size. The low-molecular-weight derivatives obtained from the sulfated fucan were employed to determine the requirement for interaction of this polysaccharide with heparin cofactor II and to achieve complete thrombin inhibition. The linear sulfated fucan requires significantly longer chains than mammalian glycosaminoglycans to achieve anticoagulant activity. A slight decrease in the molecular size of the sulfated fucan dramatically reduces its effect on thrombin inactivation mediated by heparin cofactor II. Sulfated fucan with approximately 45 tetrasaccharide repeating units binds to heparin cofactor II but is unable to link efficiently the plasma inhibitor and thrombin. This last effect requires chains with approximately 100 or more tetrasaccharide repeating units. We speculate that the template mechanism may predominate over the allosteric effect in the case of the linear sulfated fucan inactivation of thrombin in the presence of heparin cofactor II. 相似文献
9.
Vitor H. Pomin 《Glycoconjugate journal》2014,31(5):341-344
Sulfated polysaccharides, like the glycosaminoglycan (GAG) heparin, are known to exhibit anticoagulant properties when certain structural features are present. The structural requirement for this action is well-established for heparin, in which a pentasaccharide motif plays a key role for keeping the high-affinity interaction to antithrombin. Over the last years of this glycomic era, several novel anticoagulant sulfated glycans have been described. Those from marine sources have been awakening special attention mainly because of their impressive anticoagulant effects together with structural uniqueness. The commonest of these glycans are the sulfated fucans (SFs), the sulfated galactans (SGs), and the marine invertebrate GAGs like the fucosylated chondroitin sulfate and ascidian dermatan sulfate. Since these marine sulfated glycans do not bear within their polymeric chains the specific pentasaccharide motif of heparin, other structural features must be necessary to trigger the anticoagulant effect. The objective of this report is to present the anticoagulant motifs of the marine SFs, SGs and GAGs. 相似文献
10.
Sulphated polysaccharides have many biological functions, which depend on binding of highly specific carbohydrate structures to proteins. NMR spectroscopy is a technique capable of detailed structural elucidation of these polysaccharides, and can be used in applications ranging from routine analysis to research into covalent and conformational aspects of polysaccharide structure. This technique can be used to characterise sequence variations in heparin samples. The NMR-determined solution conformation of heparin has been used to predict binding sites on the surface of heparin-binding proteins. Sulphation patterns for dermatan sulphates of marine invertebrates have been determined. Their anticoagulant effects depend on an exact pattern of sulphate substitution. A small alteration in dermatan sulphate structure, from 4-O-sulphated to 6-O-sulphated galactosamine, leads to almost complete loss of anticoagulant activity in spite of an overall high level of sulphation. A fucosylated chondroitin sulphate isolated from sea cucumber has anticoagulant and antithrombotic activity depending on its sulphated fucose branches. The anticoagulant activity of algal fucans has been compared with that of regular, linear sulphated fucans from marine echinoderms; again high activity appears to correlate with the presence of sulphated fucose branches. 相似文献
11.
The major acidic polysaccharide from the brown alga Laminaria cichorioides is a complex and heterogeneous sulfated fucan. Its preponderant structure is a 2,3-disulfated, 4-linked alpha-fucose unit. The purified polysaccharide has a potent anticoagulant activity, as estimated by APTT assay ( approximately 40 IU/mg), which is mainly mediated by thrombin inhibition by heparin cofactor II. It also accelerates thrombin and factor Xa inhibition by antithrombin but at a lower potency. Sulfated fucan from L. cichorioides is a promising anticoagulant polysaccharide and a possible alternative for an antithrombotic compound due to its preferential heparin cofactor II-dependent activity. 相似文献
12.
Sulfated polysaccharides from the green algae Ulva conglobata were isolated and prepared by extraction in hot water, precipitation with ethanol and purification by ion-exchange and size-exclusion column chromatography. The characterizations of the sulfated polysaccharides were defined, and containing 23.04–35.20% sulfate ester groups, 10.82–14.91% uronic acid and 3.82–4.51% protein. Gas chromatography analysis shows that the sulfated polysaccharides from Ulva conglobata are mainly consisted of rhamnose with variable contents of glucose and fucose, trace amounts of xylose, glactose and mannose. The anticoagulant properties of the sulfated polysaccharides were compared with those of heparin by studying the activated partial thromboplastin time using normal human plasma. The sulfated polysaccharide from Ulva conglobata collected in Qingdao, China is the most potent among the sulfated polysaccharides tested. The mechanism of anticoagulant activity mediated by the sulfated polysaccharides is due to the direct inhibition of thrombin and the potentiation of heparin cofactor II. 相似文献
13.
Hayakawa Y Hayashi T Lee J Srisomporn P Maeda M Ozawa T Sakuragawa N 《Biochimica et biophysica acta》2000,1543(1):86-94
Eight different sulfated polysaccharides were isolated from Chlorophyta. All exhibited thrombin inhibition through a heparin cofactor II (HCII)-dependent pathway, and their effects on the inhibition of thrombin were more potent than those of heparin or dermatan sulfate. In particular, remarkably potent thrombin inhibition was found for the sulfated polysaccharides isolated from the Codiales. In the presence of these sulfated polysaccharides, both the recombinant HCII (rHCII) variants Lys(173)-->Leu and Arg(189)-->His, which are defective in interactions with heparin and dermatan sulfate, respectively, inhibited thrombin in a manner similar to native rHCII. This result indicates that the binding site of HCII for each of these eight sulfated polysaccharides is different from the heparin- or dermatan sulfate-binding site. All the sulfated polysaccharides but RS-2 significantly stimulated the inhibition of thrombin by an N-terminal deletion mutant of HCII (rHCII-Delta74). Furthermore, hirudin(54-65) decreased only 2-5-fold the rate of thrombin inhibition by HCII stimulated by the sulfated polysaccharides, while HD22, a single-stranded DNA aptamer that binds exosite II of thrombin, produced an approximately 10-fold reduction in this rate. These results suggest that, unlike heparin and dermatan sulfate, the sulfated polysaccharides isolated from Chlorophyta activate HCII primarily by an allosteric mechanism different from displacement and template mechanisms. 相似文献
14.
Wenjun Mao Hongyan Li Yi Li Huijuan Zhang Xiaohui Qi Haihong Sun Yin Chen Shoudong Guo 《International journal of biological macromolecules》2009,44(1):70-74
A polysaccharide was isolated from marine green algae Monostroma latissimum, and its chemical characteristic and anticoagulant activity were investigated. The results demonstrated that the polysaccharide was high rhamnose-containing sulfated polysaccharide, and was mainly composed of 1,2-linked l-rhamnose residues with sulfate groups substituted at positions C-3 and/or C-4. The sulfated polysaccharide exhibited high anticoagulant activities by assays of the activated partial thromboplastin time (APTT) and thrombin time (TT). The anticoagulant property of the sulfated polysaccharide was mainly attributed to powerful potentiation thrombin by heparin cofactor II. 相似文献
15.
Effect of (1-->3)- and (1-->4)-linkages of fully sulfated polysaccharides on their anticoagulant activity 总被引:2,自引:0,他引:2
Chaidedgumjorn A Toyoda H Woo ER Lee KB Kim YS Toida T Imanari T 《Carbohydrate research》2002,337(10):925-933
Chemically fully sulfated polysaccharides including xylan (-->4Xylbeta-(1-->4)Xylbeta1-->), amylose (-->4Glcalpha-(1-->4)Glcalpha1-->), cellulose (-->4Glcbeta-(1-->4)Glcbeta1-->), curdlan (-->3Glcbeta-(1-->3)Glcbeta1-->) and galactan (-->3Galbeta-(1-->3)Galbeta1-->), which have been isolated from Korean clam, were prepared, and their anticoagulant activity was investigated. The results strongly suggest that the activity might not be depending on anomeric configuration (alpha or beta) or monosaccharide species but on the glycosidic linkage, either (1-->3) or (1-->4). 1H NMR studies of these modified polysaccharides show that the neighboring sulfate groups at the C-2 and C-3 positions might have caused the conformational changes of each monosaccharide from 4C(1) to 1C(4). Furthermore, the effect of 6-sulfate residues on the anticoagulant activity was investigated using a specific desulfated reaction for the chemically fully sulfated polysaccharides. The 6-sulfate group is very important in determining anticoagulant activity of (1-->3)-linked polysaccharides, whereas the activity is not affected by presence or absence of the 6-sulfate group in (1-->4)-linked polysaccharides. 相似文献
16.
Sulfated polysaccharides exhibit many biological properties such as antiviral and anticoagulant activities. Herein, we report the antiviral activity of sulfated galactans extracted from the red sea-weed Bostrychia montagnei against herpes simplex virus types 1 (strain F and the thymidine kinase-deficient strains Field and B2006) and 2 (strain G). Two crude extracts obtained with cold and hot water as well as some fractions obtained by anion exchange chromatography, inhibited significantly the replication of the different strains of herpesviruses as determined by plaque reduction assays. The inhibitory effect of the compounds studied here took place only when they were added during the adsorption period. They were found to be highly selective antiviral substances, causing no impairment of Vero cell viability. Furthermore, they had no direct inactivating effect on virions by incubation in a virucidal assay. The antiviral activity could be correlated with the molecular weight and sulfate content of the polysaccharides. Although sulfated polysaccharides are generally endowed with anticoagulant properties, the results of the activated partial thromboplastin time and the thrombine time assays indicated that the natural sulfated polysaccharides from Bostrychia montagnei have very low anticoagulant activity, confirming that there is no relation between the antiviral and anticoagulant properties. 相似文献
17.
Heparan sulfate (HS) 6-O-endosulfatase (Sulf) catalyzes the hydrolysis of 6-O-sulfo groups from HS polysaccharides. The resultant HS has reduced sulfation levels and displays altered biological activities. The Sulfs have been associated with several cancers and developmental problems and could function as a tool for editing specific HS structures. Here, we characterize the substrate specificity of human Sulf-2 using site-specifically radiolabeled synthetic polysaccharides. The enzyme was expressed and harvested from the conditioned medium of Chinese hamster ovary cells transfected with Sulf-2 expression plasmids. The uniquely [(35)S]sulfated polysaccharides were prepared using purified recombinant HS biosynthetic enzymes. We found that Sulf-2 is particularly effective in removing the 6-O-sulfo group residing in the trisulfated disaccharide repeating unit comprising 2-O-sulfated uronic acid and N-sulfated 6-O-sulfo glucosamine, but can also hydrolyze sulfo groups from N- and 6-O-sulfated disaccharides. In addition, we found that Sulf-2 treatment significantly decreases HS's ability to bind to platelet factor 4 (PF4), a chemokine, while binding to antithrombin is maintained. Because HS-PF4 complexes are the initiating cause of heparin-induced thrombocytopenia, this finding provides a promising strategy for developing heparin therapies with reduced side effects. Further understanding of Sulf-2 activity will help elucidate HS structure-function relationships and provide a valuable tool in tailoring HS-based anticoagulant drugs. 相似文献
18.
Mariana Santana Santos Pereira Costa Leandro Silva Costa Sara Lima Cordeiro Jailma Almeida-Lima Nednaldo Dantas-Santos Kaline Dantas Magalh?es Diego Araujo Sabry Ivan Rui Lopes Albuquerque Marcia Rodrigues Pereira Edda Lisboa Leite Hugo Alexandre Oliveira Rocha 《Journal of applied phycology》2012,24(5):1159-1167
Seaweeds are a source of several biopolymers widely used in cosmetics, food, and pharmaceuticals. Among them are sulfated polysaccharides, which have several biological/pharmacological activities, such as antioxidant and anticoagulant activities. In the present study, four sulfated polysaccharides, denominated CCB-F0.3, CCB-F0.5, CCB-F1.0, and CCB-F2.0, were obtained from the chlorophyte Caulerpa cupressoides var. flabellata through proteolytic digestion, followed by acetone fractionation and molecular sieving in Sephadex G-100. Chemical analyses showed that CCB-F0.5 had the highest sulfate/sugar ratio (0.73), whereas CCB-F1.0 exhibited the lowest ratio (0.23). Polysaccharides from C. cupressoides displayed a heterogeneous constitution of monosaccharides, with galactose as the main sugar unit (except for CCB-F2.0). The presence of sulfated polysaccharides was confirmed by electrophoretic and infrared analyses. Sulfated polysaccharides showed no activity in superoxide and hydroxyl radical scavenging; however, they did demonstrate total antioxidant capacity and ferrous chelating activity. Caulerpa polysaccharides also exhibited anticoagulant activity in the intrinsic (activated partial thromboplastin time (aPTT) test) and extrinsic pathway (prothrombin time (PT) test). In the aPTT test, all polysaccharides displayed considerable dose-dependent activity. A significant result was the aPTT activity of the polysaccharides CCB-F0.3 and CCB-F0.5, which was similar to that of Clexane?, a commercial low molecular weight heparin. In addition, CCB-F0.3 and CCB-F0.5 showed PT activity. Sulfated polysaccharides from C. cupressoides are therefore promising antioxidant agents in preventing the formation of reactive oxygen species and for their possible use in anticoagulant therapy. 相似文献
19.
Pereira MG Benevides NM Melo MR Valente AP Melo FR Mourão PA 《Carbohydrate research》2005,340(12):2015-2023
Marine red algae are an abundant source of sulfated galactans with potent anticoagulant activity. However, the specific structural motifs that confer biological activity remain to be elucidated. We have now isolated and purified a sulfated galactan from the marine red alga, Gellidium crinale. The structure of this polysaccharide was determined using NMR spectroscopy. It is composed of the repeating structure -4-alpha-Galp-(1-->3)-beta-Galp1--> but with a variable sulfation pattern. Clearly 15% of the total alpha-units are 2,3-di-sulfated and another 55% are 2-sulfated. No evidence for the occurrence of 3,6-anhydro alpha-galactose units was observed in the NMR spectra. We also compared the anticoagulant activity of this sulfated galactan with a polysaccharide from the species, Botryocladia occidentalis, with a similar saccharide chain but with higher amounts of 2,3-di-sulfated alpha-units. The sulfated galactan from G. crinale has a lower anticoagulant activity on a clotting assay when compared with the polysaccharide from B. occidentalis. When tested in assays using specific proteases and coagulation inhibitors, these two galactans showed significant differences in their activity. They do not differ in thrombin inhibition mediated by antithrombin, but in assays where heparin cofactor II replaces antithrombin, the sulfated galactan from G. crinale requires a significantly higher concentration to achieve the same inhibitory effect as the polysaccharide from B. occidentalis. In contrast, when factor Xa instead of thrombin is used as the target protease, the sulfated galactan from G. crinale is a more potent anticoagulant. These observations suggest that the proportion and/or the distribution of 2,3-di-sulfated alpha-units along the galactan chain may be a critical structural motif to promote the interaction of the protease with specific protease and coagulation inhibitors. 相似文献