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Joachim Thiem - One of the best experts on this subject based on the ideXlab platform.
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Subsequent Enzymatic Galactosylation and Sialylation Towards Sialylated Thomsen–Friedenreich Antigen Components
Advanced Synthesis & Catalysis, 2006Co-Authors: Lars Kröger, Agnes Scudlo, Joachim ThiemAbstract:Sialyloligosaccharides of the type Neu5 Acα2-3Galβ1-3GalNAc and a range of corresponding motifs play an important role in nature and are found in gangliosides, Lewis type I structures and the sialyl-Thomsen-Friedenreich Antigen occurring in higher animals, viruses, bacteria, protozoa and pathogenic fungi. There is considerable interest to evaluate the significant functionalities of these glycostructures, and here we present a chemoenzymatic approach by a facile synthesis of such motifs. Employing chemoenzymatic methods, several modified Galβ1-3GalNAc derivatives were synthesized. Modifications were introduced at the stage of the monomeric building blocks prior to formation of the disaccharides by means of four different β-galactosidases from bovine testes, Bacillus circulans and Xanthomonas manihotis as well as the phosphorylase from Bifidobacterium bifidum. Finally, the modified disaccharide derivatives could be efficiently sialylated using the recombinant trans-sialidase from Trypanosoma cruzi.
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Facile One‐Step Syntheses of Modified O‐Glycoprotein Galβ1‐3GalNAc Structures by Transglycosylation Employing Three β‐Galactosidases from Bovine Testes, Xanthomonas manihotis, and Bacillus circulans *
Journal of Carbohydrate Chemistry, 2005Co-Authors: Lars Kröger, Joachim ThiemAbstract:Natural O‐glycoproteins such as the Thomsen‐Friedenreich Antigen or gangliosides contain the motif Galβ1‐3GalNAc as an important disaccharide with significant biologic activity. The arrangement of spatial functionalities in this structure are of particular interest with regard to the development of potential leads en route to pharmaceuticals. Therefore, it was desired to obtain access to a range of modified derivatives of the aforementioned motif paying particular attention to introducing specific deoxy functions instead of hydroxyl groups. *This paper is dedicated to Prof. Rosa M. de Lederkremer, Buenos Aires, on the occasion of her 70th anniversary in recognition of her substantial contributions to carbohydrate chemistry.
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Multienzyme System for Synthesis of the Sialylated Thomsen–Friedenreich Antigen Determinant
European Journal of Organic Chemistry, 1999Co-Authors: Ulrike Gambert, Joachim ThiemAbstract:A combined sequential use of β-galactosidase from bovine testes together with α2–3-sialyltransferase from porcine liver including cofactor regeneration transforms GalNAcα1–OThr by a multistep one-pot reaction into the sialylated Thomsen–Friedenreich Antigen determinant Neu5Acα2–3Galβ1–3GalNAcα1-OThr.
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multienzyme system for synthesis of the sialylated thomsen friedenreich Antigen determinant
European Journal of Organic Chemistry, 1999Co-Authors: Ulrike Gambert, Joachim ThiemAbstract:A combined sequential use of β-galactosidase from bovine testes together with α2–3-sialyltransferase from porcine liver including cofactor regeneration transforms GalNAcα1–OThr by a multistep one-pot reaction into the sialylated Thomsen–Friedenreich Antigen determinant Neu5Acα2–3Galβ1–3GalNAcα1-OThr.
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Chemoenzymatic synthesis of the Thomsen-Friedenreich Antigen determinant
Carbohydrate research, 1997Co-Authors: Ulrike Gambert, Joachim ThiemAbstract:Abstract The efficient chemoenzymatic synthesis of the Thomsen-Friedenreich Antigen determinant is demonstrated under transglycosylation conditions employing β-galactosidase from bovine testes.
Lothar Elling - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of the Thomsen-Friedenreich-Antigen (TF-Antigen) and binding of Galectin-3 to TF-Antigen presenting neo-glycoproteins
Glycoconjugate Journal, 2020Co-Authors: Marius Hoffmann, Marc R. Hayes, Jörg Pietruszka, Lothar EllingAbstract:The Thomsen-Friedenreich-Antigen, Gal(β1–3)GalNAc(α1- O -Ser/Thr (TF-Antigen), is presented on the surface of most human cancer cell types. Its interaction with galectin 1 and galectin 3 leads to tumor cell aggregation and promotes cancer metastasis and T-cell apoptosis in epithelial tissue. To further explore multivalent binding between the TF-Antigen and galectin-3, the TF-Antigen was enzymatically synthesized in high yields with GalNAc(α1-EG3-azide as the acceptor substrate by use of the glycosynthase BgaC/Glu233Gly. Subsequently, it was coupled to alkynyl-functionalized bovine serum albumin via a copper(I)-catalyzed alkyne-azide cycloaddition. This procedure yielded neo-glycoproteins with tunable glycan multivalency for binding studies. Glycan densities between 2 and 53 glycan residues per protein molecule were obtained by regulated alkynyl-modification of the lysine residues of BSA. The number of coupled glycans was quantified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and a trinitrobenzene sulfonic acid assay. The binding efficiency of the neo-glycoproteins with human galectin-3 and the effect of multivalency was investigated and assessed using an enzyme-linked lectin assay. Immobilized neo-glycoproteins of all modification densities showed binding of Gal-3 with increasing glycan density. However, multivalent glycan presentation did not result in a higher binding affinity. In contrast, inhibition of Gal-3 binding to asialofetuin was effective. The relative inhibitory potency was increased by a factor of 142 for neo-glycoproteins displaying 10 glycans/protein in contrast to highly decorated inhibitors with only 2-fold increase. In summary, the functionality of BSA-based neo-glycoproteins presenting the TF-Antigen as multivalent inhibitors for Gal-3 was demonstrated.
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Synthesis of the Thomsen-Friedenreich-Antigen (TF-Antigen) and binding of Galectin-3 to TF-Antigen presenting neo-glycoproteins
Glycoconjugate Journal, 2020Co-Authors: Marius Hoffmann, Marc R. Hayes, Jörg Pietruszka, Lothar EllingAbstract:The Thomsen-Friedenreich-Antigen, Gal(β1–3)GalNAc(α1- O -Ser/Thr (TF-Antigen), is presented on the surface of most human cancer cell types. Its interaction with galectin 1 and galectin 3 leads to tumor cell aggregation and promotes cancer metastasis and T-cell apoptosis in epithelial tissue. To further explore multivalent binding between the TF-Antigen and galectin-3, the TF-Antigen was enzymatically synthesized in high yields with GalNAc(α1-EG3-azide as the acceptor substrate by use of the glycosynthase BgaC/Glu233Gly. Subsequently, it was coupled to alkynyl-functionalized bovine serum albumin via a copper(I)-catalyzed alkyne-azide cycloaddition. This procedure yielded neo-glycoproteins with tunable glycan multivalency for binding studies. Glycan densities between 2 and 53 glycan residues per protein molecule were obtained by regulated alkynyl-modification of the lysine residues of BSA. The number of coupled glycans was quantified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and a trinitrobenzene sulfonic acid assay. The binding efficiency of the neo-glycoproteins with human galectin-3 and the effect of multivalency was investigated and assessed using an enzyme-linked lectin assay. Immobilized neo-glycoproteins of all modification densities showed binding of Gal-3 with increasing glycan density. However, multivalent glycan presentation did not result in a higher binding affinity. In contrast, inhibition of Gal-3 binding to asialofetuin was effective. The relative inhibitory potency was increased by a factor of 142 for neo-glycoproteins displaying 10 glycans/protein in contrast to highly decorated inhibitors with only 2-fold increase. In summary, the functionality of BSA-based neo-glycoproteins presenting the TF-Antigen as multivalent inhibitors for Gal-3 was demonstrated.
Ulrike Gambert - One of the best experts on this subject based on the ideXlab platform.
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Multienzyme System for Synthesis of the Sialylated Thomsen–Friedenreich Antigen Determinant
European Journal of Organic Chemistry, 1999Co-Authors: Ulrike Gambert, Joachim ThiemAbstract:A combined sequential use of β-galactosidase from bovine testes together with α2–3-sialyltransferase from porcine liver including cofactor regeneration transforms GalNAcα1–OThr by a multistep one-pot reaction into the sialylated Thomsen–Friedenreich Antigen determinant Neu5Acα2–3Galβ1–3GalNAcα1-OThr.
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multienzyme system for synthesis of the sialylated thomsen friedenreich Antigen determinant
European Journal of Organic Chemistry, 1999Co-Authors: Ulrike Gambert, Joachim ThiemAbstract:A combined sequential use of β-galactosidase from bovine testes together with α2–3-sialyltransferase from porcine liver including cofactor regeneration transforms GalNAcα1–OThr by a multistep one-pot reaction into the sialylated Thomsen–Friedenreich Antigen determinant Neu5Acα2–3Galβ1–3GalNAcα1-OThr.
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Chemoenzymatic synthesis of the Thomsen-Friedenreich Antigen determinant
Carbohydrate research, 1997Co-Authors: Ulrike Gambert, Joachim ThiemAbstract:Abstract The efficient chemoenzymatic synthesis of the Thomsen-Friedenreich Antigen determinant is demonstrated under transglycosylation conditions employing β-galactosidase from bovine testes.
Uwe Karsten - One of the best experts on this subject based on the ideXlab platform.
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What controls the expression of the core-1 (Thomsen-Friedenreich) glycotope on tumor cells?
Biochemistry. Biokhimiia, 2015Co-Authors: Uwe Karsten, Steffen GoletzAbstract:Malignant transformation is tightly connected with changes in the glycosylation of proteins and lipids, which in turn are contributing to the invasive and metastatic behavior of tumor cells. One example of such changes is demasking of the otherwise hidden core-1 structure, also known as Thomsen-Friedenreich Antigen, which is a highly tumor-specific glycotope and potentially a cancer stem cell marker. This review summarizes what is known about the mechanism(s) of its expression on tumor cells. New data reveal a close connection between tumor metabolism and Golgi function. Based on these data, we suggest that the expression of this Antigen is also a marker of aerobic glycolysis.
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Expression of CD176 (Thomsen‐Friedenreich Antigen) on lung, breast and liver cancer‐initiating cells
International journal of experimental pathology, 2010Co-Authors: Wei-ming Lin, Steffen Goletz, Uwe Karsten, Ruo-chuan Cheng, Yi CaoAbstract:The cancer-initiating capacity of most malignant tumours is considered to reside in a small subpopulation of cells. Therapeutical interventions should target these cells rather than the tumour mass. Numerous studies have shown that the carbohydrate Antigen structure CD176 (Thomsen-Friedenreich Antigen, core-1) is present in many types of cancer and absent in normal adult human tissues. In this study, we assessed whether CD176 is co-expressed with CD44 or CD133 [markers of cancer-initiating cells (CIC)] in human lung, breast and liver carcinoma. A variety of human cancer cell lines and surgical specimens of these malignancies were examined. It was found that in most cases the majority of tumour cells stained strongly for CD44 by immunohistochemistry and flow cytometry, whereas CD133 expression was found on a smaller, but varying proportion of cells. Co-expression of CD176 with CD44 was found at a surprisingly high percentage of cancer cells in vitro and in vivo. Co-expression of CD176 with CD133 was also detected, although at a lower rate. Tamoxifen treatment of MDA-435 breast cancer cells enhanced the CD44(+) /CD176(+) phenotype. Evidence is provided through a new sandwich solid-phase enzyme-linked immunosorbent assay (ELISA) suggesting that CD44 is a carrier molecule for CD176 not only in colorectal cancer as previously reported, but also in lung, breast and liver cancer. The expression of CD176 in CIC suggests that it may represent an effective target for tumour therapies.
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Prognostic impact of Thomsen-Friedenreich tumor Antigen and disseminated tumor cells in the bone marrow of breast cancer patients.
Breast cancer research and treatment, 2006Co-Authors: Christian Schindlbeck, Uwe Karsten, Brigitte Rack, Udo Jeschke, Sandra Schulze, Wolfgang Janni, Stan Krajewski, Harald Sommer, Klaus FrieseAbstract:Purpose The Thomsen–Friedenreich Antigen (TF, CD176) is a specific oncofetal carbohydrate epitope (Galβ1-3GalNAcα-O-Ser/Thr) expressed on the surface of various carcinomas. It mediates endothelium adhesion and formation of metastases. As it also causes immune response, its prognostic impact is indeterminate. The presence of disseminated tumor cells in the bone marrow of breast cancer patients (DTC-BM) indicates worse prognosis. We examined the expression of TF in primary breast cancer tissue of 265 patients with known BM status at the time of first diagnosis.
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Thomsen-Friedenreich Antigen: the "hidden" tumor Antigen.
Advances in experimental medicine and biology, 2003Co-Authors: Steffen Goletz, Y. Cao, Antje Danielczyk, Peter Ravn, U. Schoeber, Uwe KarstenAbstract:Carbohydrate tumor Antigens on glycoproteins and glycolipids are targets for active and passive cancer immunotherapy. These highly abundant Antigens are de novo expressed or up-regulated due to changes in the complex glycosylation apparatus of tumor cells, involving sets of enzymes like glycosyltransferases, glycosidases, epimerases, and nucleotide sugar transporters. Various lipid or protein bound carbohydrate tumor Antigens are described, for example, GM2, GD2, GD3, fucosylated GM1, Globo H, LeY, Lea, Sialyl-Lea and the mucin core structures Tn, Sialyl-Tn, and the Thomsen-Friedenreich Antigen (TF). Carbohydrate tumor Antigens are far more abundant than protein tumor Antigens rendering them suitable targets especially for antibodies, for example, highly expressed protein tumor markers as Her-2/neu express about 106 and TF about 107 copies per cell. More recent data show that certain carbohydrate structures are not only targets for humoral but also cellular immune responses.
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Inhibition of liver metastases from neuraminidase-treated colon 26 cells by an anti-Thomsen-Friedenreich-specific monoclonal antibody.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 1999Co-Authors: Hironori Shigeoka, Uwe Karsten, Kiyotaka Okuno, Masayuki YasutomiAbstract:Thomsen-Friedenreich Antigen (TF; Galβ1-3GalNAcα1-) is expressed on many human carcinomas. Evidence suggests that TF-carrying tumor cells specifically bind asialoglycoprotein receptors on hepatocytes resulting in metastasis formation in the liver. We used an animal model to examine the feasibility of preventing metastasis formation by an antibody to TF. Treatment of Colon 26 cells with neuraminidase led to the exposure of TF, and consequently to a higher frequency of liver metastases in syngeneic Balb/c mice. This could be prevented by an antibody to TF (A78-G/A7), but not by a control antibody. The results may open up a new strategy for the prophylaxis of metastatic spread to the liver.
Marius Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of the Thomsen-Friedenreich-Antigen (TF-Antigen) and binding of Galectin-3 to TF-Antigen presenting neo-glycoproteins
Glycoconjugate Journal, 2020Co-Authors: Marius Hoffmann, Marc R. Hayes, Jörg Pietruszka, Lothar EllingAbstract:The Thomsen-Friedenreich-Antigen, Gal(β1–3)GalNAc(α1- O -Ser/Thr (TF-Antigen), is presented on the surface of most human cancer cell types. Its interaction with galectin 1 and galectin 3 leads to tumor cell aggregation and promotes cancer metastasis and T-cell apoptosis in epithelial tissue. To further explore multivalent binding between the TF-Antigen and galectin-3, the TF-Antigen was enzymatically synthesized in high yields with GalNAc(α1-EG3-azide as the acceptor substrate by use of the glycosynthase BgaC/Glu233Gly. Subsequently, it was coupled to alkynyl-functionalized bovine serum albumin via a copper(I)-catalyzed alkyne-azide cycloaddition. This procedure yielded neo-glycoproteins with tunable glycan multivalency for binding studies. Glycan densities between 2 and 53 glycan residues per protein molecule were obtained by regulated alkynyl-modification of the lysine residues of BSA. The number of coupled glycans was quantified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and a trinitrobenzene sulfonic acid assay. The binding efficiency of the neo-glycoproteins with human galectin-3 and the effect of multivalency was investigated and assessed using an enzyme-linked lectin assay. Immobilized neo-glycoproteins of all modification densities showed binding of Gal-3 with increasing glycan density. However, multivalent glycan presentation did not result in a higher binding affinity. In contrast, inhibition of Gal-3 binding to asialofetuin was effective. The relative inhibitory potency was increased by a factor of 142 for neo-glycoproteins displaying 10 glycans/protein in contrast to highly decorated inhibitors with only 2-fold increase. In summary, the functionality of BSA-based neo-glycoproteins presenting the TF-Antigen as multivalent inhibitors for Gal-3 was demonstrated.
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Synthesis of the Thomsen-Friedenreich-Antigen (TF-Antigen) and binding of Galectin-3 to TF-Antigen presenting neo-glycoproteins
Glycoconjugate Journal, 2020Co-Authors: Marius Hoffmann, Marc R. Hayes, Jörg Pietruszka, Lothar EllingAbstract:The Thomsen-Friedenreich-Antigen, Gal(β1–3)GalNAc(α1- O -Ser/Thr (TF-Antigen), is presented on the surface of most human cancer cell types. Its interaction with galectin 1 and galectin 3 leads to tumor cell aggregation and promotes cancer metastasis and T-cell apoptosis in epithelial tissue. To further explore multivalent binding between the TF-Antigen and galectin-3, the TF-Antigen was enzymatically synthesized in high yields with GalNAc(α1-EG3-azide as the acceptor substrate by use of the glycosynthase BgaC/Glu233Gly. Subsequently, it was coupled to alkynyl-functionalized bovine serum albumin via a copper(I)-catalyzed alkyne-azide cycloaddition. This procedure yielded neo-glycoproteins with tunable glycan multivalency for binding studies. Glycan densities between 2 and 53 glycan residues per protein molecule were obtained by regulated alkynyl-modification of the lysine residues of BSA. The number of coupled glycans was quantified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and a trinitrobenzene sulfonic acid assay. The binding efficiency of the neo-glycoproteins with human galectin-3 and the effect of multivalency was investigated and assessed using an enzyme-linked lectin assay. Immobilized neo-glycoproteins of all modification densities showed binding of Gal-3 with increasing glycan density. However, multivalent glycan presentation did not result in a higher binding affinity. In contrast, inhibition of Gal-3 binding to asialofetuin was effective. The relative inhibitory potency was increased by a factor of 142 for neo-glycoproteins displaying 10 glycans/protein in contrast to highly decorated inhibitors with only 2-fold increase. In summary, the functionality of BSA-based neo-glycoproteins presenting the TF-Antigen as multivalent inhibitors for Gal-3 was demonstrated.