Expansion of Glycogene Members Involved in the Biosynthesis of Glycoprotein Sugar Chains

 Protein-bound oligosaccharides are assembled within cell organella consisting of endoplasmic reticulum and Golgi apparatus where glycosyltransferases and trimming glycosidases are arranged in the order of oligosaccharide sequences to be formed. It has been believed for a long time that each glycosidic linkage is formed by one single enzyme. Based on this assumption, more than 250 different glycogenes are required for constructing carbohydrate moieties of glycoconjugates in vertebrates. The total number of glycogenes that govern a glycoworld, however, is increasing day after day. This is partly due to the findings of extra-glycosyltransferases sharing similar acceptor specificities with existing transferases.

Although the biological significance of the presence of multiple glycosyltransferases with a similar acceptor specificity is not well understood, a minute difference in their acceptor specificities if this is the case may contribute to creating oligosaccharides with more specific and reproducible structures. In this respect, the concerted action of multiple peptide:N-acetylgalactosaminyltransferases only gives rise to highly clustered O-linked sugar chains on a peptide backbone.

Furthermore, in the case of sialylation of N-acetylgalactosamine residues attached to Ser or Thr residues of peptides there are at least three different a-2,6-sialyltransferases (STGalNAcs). These enzymes possess slightly different acceptor specificities and, thereby, can produce O-linked sugar chains with the Siaa2--6GalNAc-Ser/Thr, Galb1--3(Siaa2--6)GalNAc-Ser/Thr and Siaa2--3Galb1--3(Siaa2--6)GalNAc-Ser/Thr structures, respectively. Among b-1,3-galactosyltransferases I, II and III, they showed a slight difference in affinity towards UDP-Gal and N-acetylglucosamine. In the case of b-1,4-galactosyltransferase, five additional genes sharing homology with the existing gene have been discovered to encode functional transferases (b-1,4-GalTs II, III, IV, V and VI) whose fine acceptor specificities are currently under investigation. Among them, b-1,4-GalTs I and II can synthesize lactose in the presence of a-lactalbumin, but no b-1,4-GalT II transcript is detected in the mammary gland. Although these multiple enzymes can create a glycosidic linkage in vitro, there is no evidence as to where these glycosyltransferases localize in Golgi apparatus, in the same compartment or not. If they align differently in the oligosaccharide assembly line, it may reflect structural differences in oligosaccharides bound to a peptide or bound among proteins. Therefore, it is quite important to show the fine localization of each member of a glycosyltransferase family using specific monoclonal antibodies at the electron microscopic level.

One of the prominent features of glycoprotein sugar chains is organ- or species-specific structures which are brought about by differences in a set of glycosyltransferases expressed. a-Mannosidase II is involved in the processing of hybrid-type oligosaccharides to complex-type. It has been shown that a defect of a-mannosidase II from humans leads to abnormal differentiation of erythroblasts, causeing severe anemia. Targeted inactivation of mouse a-mannosidase II gene resulted in mice lacking complex-type oligosaccharides in erythrocytes and developing anemia. Quite interestingly, this mouse can synthesize complex-type oligosaccharides in tissues other than erythroblasts by another newly found a-mannosidase II, named a-mannosidase III.

In this way, ablation of mouse glycogenes is often accompanied by findings of other extra-enzymes with an acceptor specificity similar to that of the existing enzyme. Such a complicated system for glycosylation enabled the transition from single cell organisms to the primitive multicellular organism in which cell surface carbohydrates are essential for cell aggregation, i.e. multicellularity. In this section, current knowledge on our glycosylation machinery, especially glycosyltransferases, is provided.
Kiyoshi Furukawa (Department of Biosignal Research, Tokyo Metropolitan Institute of Gerontology)
Sep.15, 1998

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