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19 Marine Sulfated Polysaccharides with an Unusual Regular Inhibitors-Independent Anticoagulant Mechanism Bianca F. Glauser, Paulo A.S. Mourão, and Vitor H. Pomin
Contents 19.1 Introduction into Marine Sulfated Polysaccharides: Chemistry and Medical Uses............................................................................................267 19.2 Fucosylated Chondroitin Sulfate from Sea Cucumber L. grisea............272 19.2.1 General Structure and Anticoagulant Properties........................272 19.2.2 Extraction Methods...................................................................... 274 19.3 Sulfated Galactan from Botriocladia occidentalis.................................275 19.3.1 General Structure and Anticoagulant Properties........................275 19.3.2 Extraction Methods......................................................................276 19.4 The Most Desirable Biomedical Use for MSP Concerns Interventions on Blood Coagulation......................................................277 19.4.1 High Incidence of Cardiovascular Diseases................................277 19.4.2 Biochemical Mechanisms of Coagulation and Thrombosis........279 19.4.3 Classical Mechanism of Serpin-Dependent Inhibition................284 19.5 Complementary Serpin-Independent Anticoagulant Mechanism..........288 19.6 Advantages in the Medicinal Use of FucCS and SG over Other SPs.....291 References........................................................................................................293
19.1 Introduction into marine sulfated polysaccharides: chemistry and medical uses The efforts in both structural and biofunctional studies of marine sulfated polysaccharides (MSPs) have been increasing significantly along the last two decades (Pomin 2009a; Pomin and Mourão 2008). This attention is a consequence of the large interest in novel sulfated polysaccharides (SPs) such 267
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as glycosaminoglycans (GAGs), sulfated fucans (SFs), and sulfated galactans (SGs) that may bring out structures as novel as therapeutic mechanisms for illness treatment, especially those involved in the cardiovascular deregulations. Hence, the sea already proved to be a new and rich environment for such intersectional research of glycobiology and pharmacology, thus offering with great perspectives potential molecular candidates concerning (1) differentiated structures and (2) new pharmacological effects. This chapter strikingly exemplifies these two topics at a single report.
AQ1
Glycosaminoglycans are of particular interest to researchers due to their extreme broad range of biological actions, especially those for clinical purposes exemplified by the therapeutic applications of heparin and chondroitin sulfates (CSs). The former is the most clinically exploited anticoagulant over the last 50 years (Fareed et al. 2000), and the latter is an effective supplement for cartilage regeneration and/or revigoration. Until the early 1990s, SFs, homopolymers composed of fucopyranosyl (Fucp) units exclusively in α-lform (Pomin 2009a; Pomin and Mourão 2008), and SGs, homopolymers of α-lor α-d- and/or β-d-galactopyranosyl (Galp) units (Pomin 2009b), were usually extracted and characterized from the cell walls of the three major groups of macroalgae. Phaeophyta (brown algae) expresses SFs while both Rhodophyta (red algae) and Chlorophyta (green algae) express SGs only. Historically algal SFs and SGs are used mainly in clinical tests and large-scale extractions for industrial purposes. Actually, the greatest interest in the use and research of these molecules concerns their therapeutic effects (Pomin 2011). Recently however newer and interesting sources of these compounds have been found in the extracellular matrices of certain marine invertebrates (Mourão 2004, 2007; Mourão and Pereira, 2009; Pomin, 2008, 2009a,b; Pomin and Mourão, 2008). In contrast with most algal SPs, the invertebrate polymers exhibit highly regular chemical structures (Figure 19.1 and 19.2 A through D), which make the correlation of their biological functions to their respective structural features easier (Pomin 2009a; Pomin and Mourão 2008; Vilela-Silva et al. 2008). This is of tremendous benefit and contribution to the entire field of glycobiology. At one time it was relatively hard to accurately correlate the structure– activity relationship for the majority of SPs, especially those from mammalian sources. This advantage in use with marine sources is also observed for some marine invertebrate GAGs (Figure 2F). Unlikely some marine GAGs, many mammalian GAGs exhibit a large variety of sulfation patterns (Gandhi and Mancera 2008) and consequentially demand much more effort to understand their biological activities, determine their specific structural features, and subsequently propose a reliable structure–function relationship. These polysaccharides are composed of α-l-fucopyranosyl units (orange squares). The species-specific structures vary in sulfation patterns (exclusively 2- and/or 4-positions, in glycosidic linkages: α(1 → 3) (A–C, E, F, and H) and α(1 → 4) (D and G), and in number of residues of the repetitive units: tetrasaccharides (A–D), trisaccharides (F), and monosaccharides (E, G, and H), but they are all linear. The numbers and Greek letters over the black lines represent the 268
Bianca F. Glauser, Paulo A.S. Mourão, and Vitor H. Pomin
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A L. grisea α3
α3
α3
α3
2,4S
2S
2S
n
4S
n
2S
n
2S
n
B L. variegatus α3
α3
α3
α3
2S
2,4S
2S
C S. pallidus α3
α3 4S
α3
α3 4S
2S
D A. lixula α4
α4
α4
α4 2S
E S. purpuratus I F
S. purpuratus II
α3
α3 n 2,4S (80%) G S. droebachiensis
α4
α3
α3 2,4S
4S
4S
n
H S. franciscanus α3
2S
n
2S
n
L-Fucp
Figure 19.1 Chemical structures of repeating units of the SFs from the cell wall of the sea-cucumber (A) and from the egg jelly coat of sea-urchins (B–H).
glycosodic linkage type. The numbers before S represent the sulfation position. The structures are the following: (A) Ludwigothurea grisea [→3)-α- l-Fucp-2,4 ( OSO3− ) -(1 → 3)-α- l-Fucp-(1 → 3)-α-l-Fucp-2 ( OSO3− ) -(1 → 3)-α-l-Fucp-2 ( OSO3− ) -(1 → ]n (Mulloy et al. 1994); (B) Lytechinus variegatus [→3)-α-lFucp-2,4 ( OSO3− ) -(1 → 3)-α-l-Fucp-2 ( OSO3− ) -(1 → 3)-α-l-Fucp-2 ( OSO3− ) -(1 → 3)-α-l-Fucp-4 ( OSO3− ) -(1→]n (Mulloy et al. 1994); (C) Strongylocentrotus pallidus [→3)-α-l-Fucp-4 ( OSO3− ) -(1 → 3)-α-l-Fucp-4 ( OSO3− ) -(1 → 3)-α-l-Fucp-2 ( OSO3− ) -(1 → 3)-α-l-Fucp-2 ( OSO3− ) -(1→]n (Vilela-Silva et al. 2002); (D) Arbacia lixula [→4)-α-l-Fucp-2 ( OSO3− ) -(1 → 4)-α-l-Fucp-2 ( OSO3− ) -(1 → 4)-α-l-Fucp-(1 → 4)-α-l-Fucp-(1→]n (Alves et al. 1997); (E) Strongylocentrotus purpuratus-I Marine Sulfated Polysaccharides with an Unusual Regular Inhibitors-Independent Anticoagulant Mechanism
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A E. licunter
B G. crenularis β3
α3 2S
β3 2S
n
C H. monus
n
D S. plicata
α4
α4 3S
n
α2
3S
E α4
β3
2,4R1
2,2R3
n 1R R1, R2, and R3=OH or OSO3–
n
B.occidentalis R2=SO3–~66% R3=SO3–~33%
G. crinale R2=SO3–~60% R3=SO3–~15%
F β3
α4
2R1,3R2 3R3,6R4
n
R1, R2, R3, and R4=OH or OSO3–
R1
R2
R3
R4
S. plicata
66
