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  • 1.
    Namburi, Ramesh Babu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brittlestars Galactosaminoglycans and Tools to Study their Structure2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In all living organisms, biological activities such as proper functioning and co-ordination of different organs will depend on different cells and molecular interactions. In some organisms the loss of functional organs or damage of organs can be lethal, whereas in others a special process called regeneration can retrieve lost organs. The molecular details of regeneration are still not completely understood in many organisms. Echinoderms are close to vertebrates in the evolutionary tree and are well known for their amazing regeneration capacity. So we chose to investigate the molecular processes of regeneration mechanism with an interest towards our favorite groups of molecules, glycosaminoglycans (GAGs). GAGs are linear polysaccharides, expressed on all cell surfaces and extracellular space and are also known to be involved in many cellular activities. We aimed to characterize the GAGs present in Echinodermata species Amphiura filiformis and investigated their role during arm regeneration.

    In Paper I we characterized the structure and function of GAGs from A. filiformis and identified that A. filiformis contains CS/DS type of GAGs, but no HS. The sulfation degree of these CS/DS is close to the one of heparin, i.e. they are highly sulfated. These chains are able to bind FGF-2 growth factor and induce FGF-2 mediated cell signaling. In Paper II we further characterized these GAGs for their localization and for their role in arm regeneration in A. filiformis. Immuno- and histochemical stainings on arm sections revealed that CS/DS GAGs are localized around the podia, surrounding the water vascular system, and around the muscle tissues. Inhibition of sulfated GAG biosynthesis by chlorate treatment affected the regeneration efficiency of the arms, which may be an indication of the importance of CS/DS structures in A. filiformis arm regeneration. We also characterized some bacterial sulfatases in Paper III and a lyase in Paper IV from human and canine gut symbiotic bacteria. Here we sought to find the substrate specificity and optimal conditions for these enzymes’ activities. Our findings suggest that these polysaccharide lyase and sulfatases can be used as potential tools to characterize different GAG structures and their application could further add knowledge on diseases mechanisms related to host pathogen interactions.

     

     

     

    List of papers
    1. Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling
    Open this publication in new window or tab >>Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling
    Show others...
    2014 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 24, no 2, p. 195-207Article in journal (Refereed) Published
    Abstract [en]

    Glycosaminoglycans (GAGs) isolated from brittlestars, Echinodermata class Ophiuroidea, were characterized, as part of attempts to understand the evolutionary development of these polysaccharides. A population of chondroitin sulfate/dermatan sulfate (CS/DS) chains with a high overall degree of sulfation and hexuronate epimerization was the major GAG found, whereas heparan sulfate (HS) was below detection level. Enzymatic digestion with different chondroitin lyases revealed exceptionally high proportions of di- and trisulfated CS/DS disaccharides. The latter unit appears much more abundant in one of four individual species of brittlestars, Amphiura filiformis, than reported earlier in other marine invertebrates. The brittlestar CS/DS was further shown to bind to growth factors such as fibroblast growth factor 2 and to promote FGF-stimulated cell signaling in GAG-deficient cell lines in a manner similar to that of heparin. These findings point to a potential biological role for the highly sulfated invertebrate GAGs, similar to those ascribed to HS in vertebrates.

    Keywords
    Brittlestar, Chodroitin sulfate, Dermatan sulfate, Fibroblast growth factor-2
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-178989 (URN)10.1093/glycob/cwt100 (DOI)000330839300009 ()
    Available from: 2012-08-10 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically approved
    2. Characterization of Glycosaminoglycan (GAG) Sulfatases from the Human Gut Symbiont Bacteroides thetaiotaomicron Reveals the First GAG-specific Bacterial Endosulfatase
    Open this publication in new window or tab >>Characterization of Glycosaminoglycan (GAG) Sulfatases from the Human Gut Symbiont Bacteroides thetaiotaomicron Reveals the First GAG-specific Bacterial Endosulfatase
    Show others...
    2014 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 35, p. 24289-24303Article in journal (Refereed) Published
    Abstract [en]

    Background: Sulfatases are emerging as key adaptive tools of commensal bacteria to their host. Results: The first bacterial endo-O-sulfatase and three exo-O-sulfatases from the human commensal Bacteroides thetaiotaomicron, specific for glycosaminoglycans, have been discovered and characterized. Conclusion: Commensal bacteria possess a unique array of highly specific sulfatases to metabolize host glycans. Significance: Bacterial sulfatases are much more diverse than anticipated. Despite the importance of the microbiota in human physiology, the molecular bases that govern the interactions between these commensal bacteria and their host remain poorly understood. We recently reported that sulfatases play a key role in the adaptation of a major human commensal bacterium, Bacteroides thetaiotaomicron, to its host (Benjdia, A., Martens, E. C., Gordon, J. I., and Berteau, O. (2011) J. Biol. Chem. 286, 25973-25982). We hypothesized that sulfatases are instrumental for this bacterium, and related Bacteroides species, to metabolize highly sulfated glycans (i.e. mucins and glycosaminoglycans (GAGs)) and to colonize the intestinal mucosal layer. Based on our previous study, we investigated 10 sulfatase genes induced in the presence of host glycans. Biochemical characterization of these potential sulfatases allowed the identification of GAG-specific sulfatases selective for the type of saccharide residue and the attachment position of the sulfate group. Although some GAG-specific bacterial sulfatase activities have been described in the literature, we report here for the first time the identity and the biochemical characterization of four GAG-specific sulfatases. Furthermore, contrary to the current paradigm, we discovered that B. thetaiotaomicron possesses an authentic GAG endosulfatase that is active at the polymer level. This type of sulfatase is the first one to be identified in a bacterium. Our study thus demonstrates that bacteria have evolved more sophisticated and diverse GAG sulfatases than anticipated and establishes how B. thetaiotaomicron, and other major human commensal bacteria, can metabolize and potentially tailor complex host glycans.

    Keywords
    Bacterial Metabolism, Chondroitin Sulfate, Enzyme Mechanism, Glycosaminoglycan, Heparan Sulfate, Bacteroides thetaiotaomicron, Microbiota, Sulfatase
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-233581 (URN)10.1074/jbc.M114.573303 (DOI)000341505600025 ()
    Note

    Delad första författare för Namburi

    Delad sista författare för Spillmann

    Available from: 2014-10-13 Created: 2014-10-07 Last updated: 2017-12-05Bibliographically approved
    3. A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.
    Open this publication in new window or tab >>A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.
    Show others...
    2017 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 27, no 5, p. 438-449Article in journal (Refereed) Published
    Abstract [en]

    Glycosaminoglycans (GAGs), such as chondroitin sulfate (CS) and dermatan sulfate (DS) from various vertebrate and invertebrate sources are known to be involved in diverse cellular mechanisms during repair and regenerative processes. Recently, we have identified CS/DS as the major GAG in the brittlestar Amphiura filiformis, with high proportions of di- and tri-O-sulfated disaccharide units. As this echinoderm is known for its exceptional regeneration capacity, we aimed to explore the role of these GAG chains during A. filiformis arm regeneration. Analysis of CS/DS chains during the regeneration process revealed an increase in the proportion of the tri-O-sulfated disaccharides. Conversely, treatment of A. filiformis with sodium chlorate, a potent inhibitor of sulfation reactions in GAG biosynthesis, resulted in a significant reduction in arm growth rates with total inhibition at concentrations higher than 5 mM. Differentiation was less impacted by sodium chlorate exposure or even slightly increased at 1-2 mM. Based on the structural changes observed during arm regeneration we identified chondroitin synthase, chondroitin-4-O-sulfotransferase 2 and dermatan-4-O-sulfotransferase as candidate genes and sought to correlate their expression with the expression of the A. filiformis orthologue of bone morphogenetic factors, AfBMP2/4. Quantitative amplification by real-time PCR indicated increased expression of chondroitin synthase and chondroitin-4-O-sulfotransferase 2, with a corresponding increase in AfBMP2/4 during regeneration relative to nonregenerating controls. Our findings suggest that proper sulfation of GAGs is important for A. filiformis arm regeneration and that these molecules may participate in mechanisms controlling cell proliferation.

    Keywords
    Echinoderm, Brittlestars, Chondroitin sulfate, Dermatan sulfate, Sodium chlorate
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-178991 (URN)10.1093/glycob/cwx010 (DOI)000401003500007 ()28130266 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research CouncilSwedish Research Council FormasWenner-Gren Foundations
    Available from: 2012-08-10 Created: 2012-08-06 Last updated: 2017-06-19Bibliographically approved
    4. Chondroitinase AC: a host-associated genetic feature of Helicobacter bizzozeronii
    Open this publication in new window or tab >>Chondroitinase AC: a host-associated genetic feature of Helicobacter bizzozeronii
    2016 (English)In: Veterinary Microbiology, ISSN 0378-1135, E-ISSN 1873-2542, Vol. 186, p. 21-27Article in journal (Refereed) Published
    Abstract [en]

    Investigating mechanisms involved in host adaptation is crucial to understand pathogen evolution. Helicobacter species appear to have a host species-specific tropism, coevolving with their natural hosts, and to develop several strategies allowing the colonization of the stomach throughout lifetime of their hosts. However, little is known about genetic features associated with the adaptation to a specific animal host. In this study we discovered a polysaccharide lyase that is expressed by the canine-associated species H. bizzozeronii and acts as chondroitinase AC-type lyase of broad specificity. Except for its low pH optimum between pH 4.0 and pH 5.5, the properties of the H. bizzozeronii chondroitin lyase AC resemble the ones from Arthrobacter aurescens. However, homologues of this gene have been detected only in Helicobacter species colonizing the canine and feline gastric mucosa. Since a unique feature of the canine stomach is the secretion of chondroitin-4-sulphate in the gastric juice of the fundus mucosa by chief cells, the expression of chondroitinase AC by H. bizzozeronii is likely the consequence of adaptation of this bacterium to its host and a potential link to gastric disorders in dogs.

    Keywords
    Canine gut microbiota; Helicobactor bizzozeronii; Glycosaminoglycan lyase; Carbohydrate lyases; Chondroitin sulphate
    National Category
    Microbiology in the medical area Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Biochemistry; Microbiology; Molecular Cellbiology; Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-272079 (URN)10.1016/j.vetmic.2016.02.013 (DOI)000374709900004 ()27016753 (PubMedID)
    Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2018-01-10Bibliographically approved
  • 2.
    Namburi, Ramesh Babu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chondroitinase AC: a host-associated genetic feature of Helicobacter bizzozeroniiArticle in journal (Refereed)
  • 3.
    Namburi, Ramesh Babu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berteau, Olivier
    INRA, ChemSyBio, UMR Micalis 1319, F-78350 Jouy En Josas, France;AgroParisTech, ChemSyBio, UMR Micalis, F-78350 Jouy En Josas, France.
    Spillman, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rossi, Mirko
    Univ Helsinki, Dept Food Hyg & Environm Hlth, Fac Vet Med, POB 66,Agnes Sjobergin Katu 2, FI-00014 Helsinki, Finland.
    Chondroitinase AC: a host-associated genetic feature of Helicobacter bizzozeronii2016In: Veterinary Microbiology, ISSN 0378-1135, E-ISSN 1873-2542, Vol. 186, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Investigating mechanisms involved in host adaptation is crucial to understand pathogen evolution. Helicobacter species appear to have a host species-specific tropism, coevolving with their natural hosts, and to develop several strategies allowing the colonization of the stomach throughout lifetime of their hosts. However, little is known about genetic features associated with the adaptation to a specific animal host. In this study we discovered a polysaccharide lyase that is expressed by the canine-associated species H. bizzozeronii and acts as chondroitinase AC-type lyase of broad specificity. Except for its low pH optimum between pH 4.0 and pH 5.5, the properties of the H. bizzozeronii chondroitin lyase AC resemble the ones from Arthrobacter aurescens. However, homologues of this gene have been detected only in Helicobacter species colonizing the canine and feline gastric mucosa. Since a unique feature of the canine stomach is the secretion of chondroitin-4-sulphate in the gastric juice of the fundus mucosa by chief cells, the expression of chondroitinase AC by H. bizzozeronii is likely the consequence of adaptation of this bacterium to its host and a potential link to gastric disorders in dogs.

  • 4.
    Ramachandra, Rashmi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Namburi, Ramesh Babu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dupont, Sam
    Department of Biological and Environmental Sciences, University of Gothenburg .
    Ortega-Martinez, Olga
    Department of Biological and Environmental Sciences, University of Gothenburg .
    Thorndyke, Michael
    Department of Biological and Environmental Sciences, University of Gothenburg .
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A Potential Role for Chondroitin Sulfate/Dermatan Sulfate in Arm Regeneration in Amphiura filiformis.2017In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 27, no 5, p. 438-449Article in journal (Refereed)
    Abstract [en]

    Glycosaminoglycans (GAGs), such as chondroitin sulfate (CS) and dermatan sulfate (DS) from various vertebrate and invertebrate sources are known to be involved in diverse cellular mechanisms during repair and regenerative processes. Recently, we have identified CS/DS as the major GAG in the brittlestar Amphiura filiformis, with high proportions of di- and tri-O-sulfated disaccharide units. As this echinoderm is known for its exceptional regeneration capacity, we aimed to explore the role of these GAG chains during A. filiformis arm regeneration. Analysis of CS/DS chains during the regeneration process revealed an increase in the proportion of the tri-O-sulfated disaccharides. Conversely, treatment of A. filiformis with sodium chlorate, a potent inhibitor of sulfation reactions in GAG biosynthesis, resulted in a significant reduction in arm growth rates with total inhibition at concentrations higher than 5 mM. Differentiation was less impacted by sodium chlorate exposure or even slightly increased at 1-2 mM. Based on the structural changes observed during arm regeneration we identified chondroitin synthase, chondroitin-4-O-sulfotransferase 2 and dermatan-4-O-sulfotransferase as candidate genes and sought to correlate their expression with the expression of the A. filiformis orthologue of bone morphogenetic factors, AfBMP2/4. Quantitative amplification by real-time PCR indicated increased expression of chondroitin synthase and chondroitin-4-O-sulfotransferase 2, with a corresponding increase in AfBMP2/4 during regeneration relative to nonregenerating controls. Our findings suggest that proper sulfation of GAGs is important for A. filiformis arm regeneration and that these molecules may participate in mechanisms controlling cell proliferation.

  • 5.
    Ramachandra, Rashmi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Namburi, Ramesh Babu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ortega-Martinez, Olga
    Department of Biological and Environmental Sciences, University of Gothenburg .
    Shi, Xiaofeng
    Department of Biochemistry, Boston University.
    Zaia, Joseph
    Department of Biochemistry, Boston University.
    Dupont, Sam T.
    Department of Biological and Environmental Sciences, University of Gothenburg .
    Thorndyke, Michael
    Department of Biological and Environmental Sciences, University of Gothenburg .
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Brittlestars contain highly sulfated chondroitin sulfates/dermatan sulfates that promote fibroblast growth factor 2-induced cell signaling2014In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 24, no 2, p. 195-207Article in journal (Refereed)
    Abstract [en]

    Glycosaminoglycans (GAGs) isolated from brittlestars, Echinodermata class Ophiuroidea, were characterized, as part of attempts to understand the evolutionary development of these polysaccharides. A population of chondroitin sulfate/dermatan sulfate (CS/DS) chains with a high overall degree of sulfation and hexuronate epimerization was the major GAG found, whereas heparan sulfate (HS) was below detection level. Enzymatic digestion with different chondroitin lyases revealed exceptionally high proportions of di- and trisulfated CS/DS disaccharides. The latter unit appears much more abundant in one of four individual species of brittlestars, Amphiura filiformis, than reported earlier in other marine invertebrates. The brittlestar CS/DS was further shown to bind to growth factors such as fibroblast growth factor 2 and to promote FGF-stimulated cell signaling in GAG-deficient cell lines in a manner similar to that of heparin. These findings point to a potential biological role for the highly sulfated invertebrate GAGs, similar to those ascribed to HS in vertebrates.

  • 6. Ulmer, Jonathan E.
    et al.
    Vilen, Eric Morssing
    Namburi, Ramesh Babu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Benjdia, Alhosna
    Beneteau, Julie
    Malleron, Annie
    Bonnaffe, David
    Driguez, Pierre-Alexandre
    Descroix, Karine
    Lassalle, Gilbert
    Le Narvor, Christine
    Sandstrom, Corine
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berteau, Olivier
    Characterization of Glycosaminoglycan (GAG) Sulfatases from the Human Gut Symbiont Bacteroides thetaiotaomicron Reveals the First GAG-specific Bacterial Endosulfatase2014In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 35, p. 24289-24303Article in journal (Refereed)
    Abstract [en]

    Background: Sulfatases are emerging as key adaptive tools of commensal bacteria to their host. Results: The first bacterial endo-O-sulfatase and three exo-O-sulfatases from the human commensal Bacteroides thetaiotaomicron, specific for glycosaminoglycans, have been discovered and characterized. Conclusion: Commensal bacteria possess a unique array of highly specific sulfatases to metabolize host glycans. Significance: Bacterial sulfatases are much more diverse than anticipated. Despite the importance of the microbiota in human physiology, the molecular bases that govern the interactions between these commensal bacteria and their host remain poorly understood. We recently reported that sulfatases play a key role in the adaptation of a major human commensal bacterium, Bacteroides thetaiotaomicron, to its host (Benjdia, A., Martens, E. C., Gordon, J. I., and Berteau, O. (2011) J. Biol. Chem. 286, 25973-25982). We hypothesized that sulfatases are instrumental for this bacterium, and related Bacteroides species, to metabolize highly sulfated glycans (i.e. mucins and glycosaminoglycans (GAGs)) and to colonize the intestinal mucosal layer. Based on our previous study, we investigated 10 sulfatase genes induced in the presence of host glycans. Biochemical characterization of these potential sulfatases allowed the identification of GAG-specific sulfatases selective for the type of saccharide residue and the attachment position of the sulfate group. Although some GAG-specific bacterial sulfatase activities have been described in the literature, we report here for the first time the identity and the biochemical characterization of four GAG-specific sulfatases. Furthermore, contrary to the current paradigm, we discovered that B. thetaiotaomicron possesses an authentic GAG endosulfatase that is active at the polymer level. This type of sulfatase is the first one to be identified in a bacterium. Our study thus demonstrates that bacteria have evolved more sophisticated and diverse GAG sulfatases than anticipated and establishes how B. thetaiotaomicron, and other major human commensal bacteria, can metabolize and potentially tailor complex host glycans.

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