GDP-fucose

Leukocyte adhesion deficiency, type II (MIM 266265) Probably mutations affecting a Golgi-located GDP-fucose transporter, resulting in defective fucosylation. 

Figure 7.29 Mechanism and inhibition of human fucosyltransferases by fluoro-GDP-fucoses. ...

Fucosyltransferases (glycosyltransferases) promote the transfer of fucose from GDP-fucose onto a saccharidic acceptor. This transfer occurs with inversion of the configuration of the anomeric carbon. The inhibition has been studied with fluorinated substrates. GDP-2-fluoro-2-deoxyfucoses (GDP-2F-fucose) and GDP-6-fluoro-6-deoxyfucoses (GDP-6F-fucose) are competitive inhibitors. The values are close to or less than that of (Figure 1.29)P The very close values of GDP-2F-fucose... 

Liibke T, Marquardt T, Etzioni A, Hartmann E, von Figura K, Korner C (2001) Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat Genet 28 73-76... 

Liibke T, Marquardt T, von Figura K, Korner C (1999) A new type of carbohydrate-deficient glycoprotein syndrome due to a decreased import of GDP-fucose into the Golgi. J Biol Chem 274 25986-25989... 

Wittmann V, Wong C-H (1997) H-Tetrazole as catalyst in phosphomorpholidate coupling reactions efficient synthesis of GDP-fucose, GDP-mannose, and UDP-galactose. J Org Chem 62 2144... 

Nucleotide sugar donors, such as UDP-GalNAc, UDP-GlcNAc, GDP-fucose, and CMP-sialic acid, serve as substrates for the glycosyltransferases and are the source of the sugars that are added to substrate proteins (Table 1). Nucleotide sugar donors are synthesized in the cytoplasm and imported into the secretory pathway by membrane-resident transporters (1). 

Figure 2 Examples of glycosyl donors. Nucleotide donors are represented by UDP-galactose (UDP-Gal), GDP-fucose (GDP-Fuc), GMP-N-acetyIneuraminic acid (CMP-sialic acid, CMP-Neu5Ac), GDP-galactose (GDP-Gal), dTDP-rhamnose (dTDP-Rha), and dTDP-daunosamine lipid phosphate donors are represented by Lipid II and dolichol-phosphate-glucose (Dol-P-GIc) sugar phosphate donors are represented by glucose-1-phosphate. The saccharides are transferred from these donors by GTs to form oligo/polysaccharides and glycoconjugate products.

Fig. 8. Enzymatic fucosylation with integrated cofactor regeneration (Enzymes vi cf. Fig. 2, xi GDP-fucose-pyrophosphorylase, xii al-3/4-fucosyltransferase) [72]... 

Here again, it is as probes that carba-oligosaccharides find their best applications. Compounds 7 and 8 were both submitted to the action of a-(l-3/4)-fucosyltransferase in the presence of GDP-fucose. Only 7 was accepted and fucosylated to give the Lewis analog 9 showing that this enzyme has a different mode of action regarding the synthesis of Lewis s (Scheme 8.3) [16]. 

Cai, S, Stroud, M R, Hakomori, S, Toyokuni, T, Synthesis of carbocyclic analogs of guanosine 5 -(beta-L-fucopyranosyl diphosphate) (GDP-fucose) as potential inhibitors of fucosyltransferases, J. Org. Chem., 57, 6693-6696, 1992. 

U. B. Gokhale, O. Hindsgaul, and M. M. Palcic, Chemical synthesis of GDP-fucose analogs and their utilization by the Lewis a-l,4-fucosyltransferase. Can. J. Chem. 65 1063 (1990). 

A potent inhibitor against human a(l,3)-fucosyltransferase VI was identified from a GDP-triazole library of 85 compounds, which was produced by the Cu(I)-catalyzed [2 + 3] cycloaddition reaction between azide and acetylene, followed by in situ screening without product isolation (O Scheme 13) [155]. Kinetic evaluation of the purified inhibitor (O Scheme 13) showed that it is a competitive inhibitor against GDP-fucose with Ki = 62 nM, which would make this compound the first nanomolar and most potent inhibitor of Fuc-Ts. 

The FucT III transfers an L-fucose unit from GDP-fucose onto the 4-OH-group of a galactosylated N-acetylglucosamine in an a-niode to give the Lewis trisaccharide or the sialyl-Lewis tetrasaccharide, respectively (Fig. 13). 

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