Anticoagulant activity of a sulfated galactan: serpin-independent effect and specific interaction with factor Xa.
Research article published in Thrombosis and haemostasis (2009)
Abstract
An algal sulfated galactan has high anticoagulant and antithrombotic activities. Its serpin-dependent anticoagulant action is due to promoting thrombin and factor (F)Xa inhibition by antithrombin and heparin cofactor II. Here, we evaluated the anticoagulant effect of the algal sulfated galactan using serpin-free plasma. In contrast to heparin, the sulfated galactan is still able to prolong coagulation time and delay thrombin and FXa generation in serpin-free plasma. We further investigated this effect using purified blood coagulation proteins, discovering that sulfated galactan inhibits the intrinsic tenase and prothrombinase complexes, which are critical for FXa and thrombin generation, respectively. We also investigated the mechanism by which sulfated galactan promotes FXa inhibition by antithrombin using specific recombinant mutants of the protease. We show that sulfated galactan interacts with the heparin-binding exosite of FXa and Arg-236 and Lys-240 of this site are critical residues for this interaction, as observed for heparin. Thus, sulfated galactan and heparin have similar high-affinity and specificity for interaction with FXa, though they have differences in their chemical structures. Similar to heparin, the ability of sulfated galactan to potentiate FXa inhibition by antithrombin is calcium-dependent. However, in contrast to heparin, this effect is not entirely dependent on the conformation of the gamma-carboxyglutamic acid-rich domain of the protease. In conclusion, sulfated galactan and heparin have some similar effects on blood coagulation, but also differ significantly at the molecular level. This sulfated galactan opens new perspective for the development of antithrombotic drugs.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
An algal sulfated galactan has high anticoagulant and antithrombotic activities. Its serpin-dependent anticoagulant action is due to promoting thrombin and factor (F)Xa inhibition by antithrombin and heparin cofactor II. Here, we evaluated the anticoagulant effect of the algal sulfated galactan using serpin-free plasma. In contrast to heparin, the sulfated galactan is still able to prolong coagulation time and delay thrombin and FXa generation in serpin-free plasma.
Why This Matters for Hirudotherapy
This in-vitro mechanistic study showed that an algal sulfated galactan prolongs coagulation even in serpin-free plasma, directly inhibiting the intrinsic tenase and prothrombinase complexes, and binds the heparin-binding exosite of factor Xa (with Arg-236 and Lys-240 as key residues) in a calcium-dependent way that resembles yet differs structurally from heparin, which the authors frame as a new avenue for antithrombotic drug development. For ASH this is a clean parallel to the leech-secretome drug-discovery story: it demonstrates how a non-mammalian natural polysaccharide can yield novel, mechanistically distinct anticoagulants, the same logic by which leech salivary molecules are mined as drug leads. The work is entirely preclinical, using purified proteins, recombinant mutants, and plasma rather than patients, and concerns an algal compound, not a leech-derived agent, so it supports concept-level rationale only and implies no clinical efficacy or approval.
Citation
Anticoagulant activity of a sulfated galactan: serpin-independent effect and specific interaction with factor Xa.
Glauser et al. · Thrombosis and haemostasis, 2009
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