Acceptor specificity of GDP-Fuc:Galβ1→4GlcNAc-R α3-fucosyltransferase VI (FucT VI) expressed in insect cells as soluble, secreted enzyme

Vries, Theodora de; Palcic, M.; Schoenmakers, P.S.; Eijnden, Dirk H. van den; Joziasse, David H.

doi:10.1093/glycob/7.7.921

Cited by 60 publications

(34 citation statements)

References 34 publications

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“…Second, there is no available structural information about FTs, as evidenced by the absence of X-ray crystallographic or nuclear magnetic resonance models. Third, FTs have a low affinity for GDP-fucose and acceptor substrates, calling into question the practicality in designing inhibitors that are of sufficient affinity and potency [265][266][267]. At least one molecule, compound 24, was identified from a library of 85 different GDP-triazole compounds screened against FT6 [268].…”

Section: Therapeutics Targeting Selectins and Selectin Ligandsmentioning

confidence: 99%

Targeting selectins and selectin ligands in inflammation and cancer

Barthel

Gavino

Descheny

et al. 2007

Expert Opinion on Therapeutic Targets

340

280

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Inflammation and cancer metastasis are associated with extravasation of leukocytes or tumor cells from blood into tissue. Such movement is believed to follow a coordinated and sequential molecular cascade initiated, in part, by the three members of the selectin family of carbohydrate-binding proteins: E-selectin (CD62E), L-selectin (CD62L) and P-selectin (CD62P). E-selectin is particularly noteworthy in disease by virtue of its expression on activated endothelium and on bone-skin microvascular linings and for its role in cell rolling, cell signaling and chemotaxis. E-selectin, along with L-or P-selectin, mediates cell tethering and rolling interactions through the recognition of sialofucosylated Lewis carbohydrates expressed on structurally diverse protein-lipid ligands on circulating leukocytes or tumor cells. Major advances in understanding the role of E-selectin in inflammation and cancer have been advanced by experiments assaying E-selectin-mediated rolling of leukocytes and tumor cells under hydrodynamic shear flow, by clinical models of E-selectindependent inflammation, by mice deficient in E-selectin and by mice deficient in glycosyltransferases that regulate the binding activity of E-selectin ligands. Here, the authors elaborate on how E-selectin and its ligands may facilitate leukocyte or tumor cell recruitment in inflammatory and metastatic settings. Antagonists that target cellular interactions with E-selectin and other members of the selectin family, including neutralizing monoclonal antibodies, competitive ligand inhibitors or metabolic carbohydrate mimetics, exemplify a growing arsenal of potentially effective therapeutics in controlling inflammation and the metastatic behavior of cancer.

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Section: Therapeutics Targeting Selectins and Selectin Ligandsmentioning

confidence: 99%

Targeting selectins and selectin ligands in inflammation and cancer

Barthel

Gavino

Descheny

et al. 2007

Expert Opinion on Therapeutic Targets

340

280

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“…This was confirmed in several glycosyltransferases with resolved crystal structures as reviewed previously (43). Using a panel of monodeoxygenated Type I and Type II acceptor substrates, the 6-OH of the galactose moiety in both Type I and Type II acceptors and the reactive hydroxyl group (the OH-4 and OH-3 of GlcNAc in Type I and Type II, respectively) were found to be essential for the recognition by human FucT III, IV, V (44), VI (45), and human milk ␣1,3 and ␣1, 3/4 FucTs (46,47). This suggests that Type I and Type II acceptors, when they bind to human ␣1,3 and ␣1,3/4 FucTs, most likely adopt a conformation so that the OH-4 of GlcNAc in Type I acceptor is placed in the same position relative to the 6-OH of the galactose moiety as is the OH-3 of GlcNAc in Type II acceptor.…”

Section: Discussionmentioning

confidence: 66%

A Single Aromatic Amino Acid at the Carboxyl Terminus of Helicobacter pylori α1,3/4 Fucosyltransferase Determines Substrate Specificity

Lau

Palcic

et al. 2005

Journal of Biological Chemistry

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Fucosyltransferases (FucT) from differentHelicobacter pylori strains display distinct Type I (Gal␤1,3GlcNAc) or Type II (Gal␤1,4GlcNAc) substrate specificity. FucT from strain UA948 can transfer fucose to the OH-3 of Type II acceptors as well as to the OH-4 of Type I acceptors on the GlcNAc moiety, so it has both ␣1,3 and ␣1,4 activities. In contrast, FucT from strain NCTC11639 has exclusive ␣1,3 activity. Our domain swapping study ( Helicobacter pylori is associated with gastritis and peptic ulcer formation and is a risk factor for the development of gastric cancer and mucosa-associated lymphoid tissue lymphoma. One of the virulence factors of H. pylori is the lipopolysaccharide, which contains lipid A, core oligosaccharide and O-antigens. The O-antigens of H. pylori lipopolysaccharide contain fucosylated oligosaccharides, predominantly the Type II blood group antigens, Lewis X (Gal␤1,4(Fuc␣1,3)GlcNAc) and Lewis Y (Fuc␣1,2Gal␤1,4(Fuc␣1,3)GlcNAc) (1), but a small number of H. pylori strains also express the Type I blood group antigens, Lewis A (Gal␤1,3(Fuc␣1,4)GlcNAc), and Lewis B (Fuc␣1,2Gal␤1,3(Fuc␣1,4)-GlcNAc) (2).The role of Lewis antigens in H. pylori pathogenesis is still ambiguous. It has been suggested that Lewis antigens play a role in H. pylori adhesion to (3, 4) or internalization by (5) the gastric epithelial cells. Nevertheless, conflicting evidence argues that Lewis X and Lewis Y are not required for colonization of human gastric epithelium (6) or mouse stomach (7,8). Lewis antigens may also play an important role in the persistence of H. pylori infection by molecular mimicry, helping the bacteria to evade the host immune response (2, 9, 10). Environmental changes such as pH influence the expression of H. pylori O-antigens, particularly Lewis X and Lewis Y. This may aid in adaptation of the bacterium to its niche in the stomach (10).Fucosyltransferases (FucTs) 3 are enzymes responsible for the last steps in the synthesis of Lewis antigens in H. pylori (11,12). ␣1,2 and ␣1,3 or ␣1,3/4 FucTs have been identified and characterized in H. pylori (13-18). These FucTs catalyze the transfer of the L-fucose moiety from guanosine diphosphate ␤-L-fucose (GDP-Fuc) to the OH-2 of the galactose moiety and the OH-3 or the OH-3 and the OH-4 positions of the GlcNAc moiety in glycoconjugate acceptors, respectively. The H. pylori genome contains two homologous ␣1,3 or ␣1,3/4 FucT genes, futA and futB (19,20), but they do not always encode functional proteins. For instance, only the futA gene encodes an active FucT in H. pylori strains NCTC11639 and UA948 (13,17). Bacterial ␣1,3/4 FucTs are functionally equivalent to the mammalian ␣1,3/4 FucTs, which have been well characterized. Mammalian FucTs are Type II membrane proteins with a short N-terminal cytoplasmic tail, transmembrane domain, stem region, and C-terminal catalytic domain. H. pylori FucTs share weak homology with their mammalian counterparts in two small segments within the catalytic domain, called ␣1,3 FucT motifs (14, 21). H. pylori ␣1,3/4 FucTs lack the N...

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“…However, we did not observe any differences in caspase-8 activation at DISC between mock-and GMDS-rescued cells. FUT6 catalyzes ␣1,3-fucosylation on specific acceptor substrates (29). In contrast, GMDS affects all types of fucosylation events, including ␣1,2-, 1,3-, 1,4-, 1,6-, and O-fucosylation, through the synthesis of GDP-fucose.…”

Section: Discussionmentioning

confidence: 99%

GDP-mannose-4,6-dehydratase (GMDS) Deficiency Renders Colon Cancer Cells Resistant to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor- and CD95-mediated Apoptosis by Inhibiting Complex II Formation

Moriwaki

Shinzaki

Miyoshi

2011

Journal of Biological Chemistry

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Background: An impaired TRAIL-induced apoptosis by GMDS deficiency resulted in tumor progression. Results: Caspase-8 activation at FADD-dependent complex II upon TRAIL or CD95L stimulation was inhibited by GMDS deficiency. Conclusion: GMDS regulated the transition from a primary DISC to a secondary complex II upon TRAIL or CD95L stimulation. Significance: Our findings develop a better understanding about death receptor signaling complex.

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Acceptor specificity of GDP-Fuc:Galβ1→4GlcNAc-R α3-fucosyltransferase VI (FucT VI) expressed in insect cells as soluble, secreted enzyme

Cited by 60 publications

References 34 publications

Targeting selectins and selectin ligands in inflammation and cancer

Targeting selectins and selectin ligands in inflammation and cancer

A Single Aromatic Amino Acid at the Carboxyl Terminus of Helicobacter pylori α1,3/4 Fucosyltransferase Determines Substrate Specificity

GDP-mannose-4,6-dehydratase (GMDS) Deficiency Renders Colon Cancer Cells Resistant to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor- and CD95-mediated Apoptosis by Inhibiting Complex II Formation

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