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Anticoagulant activity of a unique sulfated pyranosic (1→3)-β-L- arabinan through direct interaction with thrombin
- Source :
- J. Biol. Chem. 2013;288(1):223-233, Biblioteca Digital (UBA-FCEN), Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales, instacron:UBA-FCEN
- Publication Year :
- 2013
-
Abstract
- A highly sulfated 3-linked β-arabinan (Ab1) with arabinose in the pyranose form was obtained from green seaweed Codium vermilara (Bryopsidales). It comprised major amounts of units sulfated on C-2 and C-4 and constitutes the first polysaccharide of this type isolated in the pure form and fully characterized. Ab1 showed anticoagulant activity by global coagulation tests. Less sulfated arabinans obtained from the same seaweed have less or no activity. Ab1 exerts its activity through direct and indirect (antithrombin- and heparin cofactor II-mediated) inhibition of thrombin. Direct thrombin inhibition was studied in detail. By native PAGE, it was possible to detect formation of a complex between Ab1 and human thrombin (HT). Ab1 binding to HT was measured by fluorescence spectroscopy. CD spectra of the Ab1 complex suggested that ligand binding induced a small conformational change on HT. Ab1-thrombin interactions were studied by molecular dynamic simulations using the persulfated octasaccharide as model compound. Most carbohydrate-protein contacts would occur by interaction of sulfate groups with basic amino acid residues on the surface of the enzyme, more than 60% of them being performed by the exosite 2-composing residues. In these interactions, the sulfate groups on C-2 were shown to interact more intensely with the thrombin structure. In contrast, the disulfated oligosaccharide does not promote major conformational modifications at the catalytic site when complexed to exosite 1. These results show that this novel pyranosic sulfated arabinan Ab1 exerts its anticoagulant activity by a mechanism different from those found previously for other sulfated polysaccharides and glycosaminoglycans. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Fil:Fernández, P.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Quintana, I. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Cerezo, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estevez, J.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Ciancia, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
- Subjects :
- CD spectra
Magnetic Resonance Spectroscopy
Antithrombin
Molecular Conformation
Amino acid residues
Oligosaccharides
Arabinans
sulfated pyranosic beta arabinan
heparin cofactor II
Cell Wall
Spectroscopy, Fourier Transform Infrared
Catalytic sites
Carbohydrate Conformation
Thrombin inhibition
Fluorescence spectroscopy
anticoagulation
Ligand binding
Anticoagulant activities
Glycosaminoglycans
conformational transition
Circular Dichroism
Heparin cofactor
article
Thrombin
blood clotting test
Octasaccharide
Computer simulation
simulation
Enzymes
unclassified drug
priority journal
protein protein interaction
Sulfate groups
Amino acids
Direct interactions
amino acid
Caulerpales
Protein Binding
Pyranose
Electrophoresis
Biophysics
Methylation
Gas Chromatography-Mass Spectrometry
protein modification
Green seaweed
Polysaccharides
drug mechanism
oligosaccharide
Animals
Humans
algal extract
arabinose
Blood Coagulation
Codium vermilara
Sulfated polysaccharides
Pyrans
Coagulation
nonhuman
catalysis
Anticoagulants
Conformational change
Model compound
Seaweed
molecular dynamics
drug structure
Kinetics
Models, Chemical
carbohydrate
polysaccharide
Cattle
protein
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- J. Biol. Chem. 2013;288(1):223-233, Biblioteca Digital (UBA-FCEN), Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales, instacron:UBA-FCEN
- Accession number :
- edsair.od......3056..ea348b6464497b51bf3439632af1aa21