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Research paper : Development of basic tools for glycoscience and their application to cancer diagnosis (H. Narimatsu)−203−Synthesiology - English edition Vol.5 No.3 (2012) the individual differences of glycan structures. Mutation of the relevant glycotransferase genes induces loss of enzyme activity or alteration of substrate specificity, causing the differences in glycan structures. This mutation is inherited from parent to child. The largest obstacle of organ transplantation in humans is the difference of glycan structures concerned in the ABO blood group system.(5)Glycans have species specificity. Evolution of glycosyltransferase genes is the fastest among that of all genes. This is probably due to the fact that the glycans on the cell surface are most directly affected by the changes of the outer environment, and the glycan structures have long been selected in response to those changes. Erythropoietin being used as a pharmaceutical antibody and hematopoietics is produced by using hamster cells. Thus its glycan structures are the same as those of hamsters, not of humans. Erythropoietin could be used for doping by athletes. Therefore, testing for hamster-type glycans is applicable for doping inspections. Studies for transplantation of pig organs (xenotransplantation) have been ongoing, but acute rejection occurs due to different glycan structures, as pigs have specific glycan structures that are not found in humans.(6)In infectious disease, infection is initiated by binding of pathogenic microorganisms with specific glycans of the host cells. Many kinds of viruses including influenza virus bind to glycans. There are also opposite cases. Glycan structures of pathogenic microorganisms are recognized by and bound with lectins on the surface of the host cells, and thus the host cells become infected. The terminal end of glycans is most closely interacted with the outer environment. Infection of many pathogens begins by binding to glycans (or lectins) of cells, suggesting that the individual selection to avoid the infection from pathogens is one of the causes for the fast evolution of the glycan structures. To avoid infection genetically, alteration of glycan structures helps preserving the species. Influenza viruses bind to 2,6 sialic acid, Helicobacter pylori to Lewis-type blood group glycans, and noroviruses to ABO and Lewis-type blood group glycans. Individuals which gained tolerance against infection through mutation of glycosyltransferases survive and procreate descendants. Such individual selection can be seen for more than ten-thousand years. The ABO blood group system can be found in species upper than anthropoid, but the Lewis blood group system is specific to humans. The mutation of glycosyltransferase that specifies the Lewis blood group antigens occurred 20 to 30 thousand years ago. 3 Scenario and strategy of glycoscienceAs described above, glycan structures well reflect the differentiation and dedifferentiation (canceration) of cells, as well as tissue specificities. These characteristics serve as the principle for development of glycan biomarkers. Glycan structures are determined mainly based on the expression patterns of glycosyltransferases, and thus are estimated to be controlled by the transcriptional regulatory mechanism or epigenetic mechanisms (control of expression patterns by post-translational modification not relying on the gene sequence). However, such basic research had hardly been conducted 10 years ago. Therefore, we had to start from the development of basic technologies required for the glycoscience by ourselves, which greatly contributed to the remarkable progress of the research field. It was the most desired and attractive task to be accomplished as a pioneer of a new science. If a scientist starts research using technologies developed by a foreign country, it cannot be denied that this scientist lags behind the foreign country. This can be applicable to any of the scientific fields.In the glycoscience, likewise in the genetics and protein science, the firstly-required basic technologies are those for synthesis and structure (or sequence) analysis. These basic technologies must be easy to use for every researcher. Ten years ago, most of the available technologies for synthesis and structure analysis were immature and inappropriate for non-expertized users. Therefore, we set a 10-year perspective to pursue the sequential approach for glycoscience (Fig.2). We focused on the development of basic technologies during the first 5 years, and then application of the technologies during the latter 5 years. The process of research was as follows: (1) Human-derived glycogenes were comprehensively identified and analyzed. (2) Recombinant glycosyltransferases were expressed from the obtained glycogenes, and obtained enzymes were used in combination to synthesize glycans with a variety of structures to make a glycan library. (3) Obtained glycans with known structures were used as the standards for development of glycan analysis technologies. (4) In vivo functions of glycans were analyzed.To elucidate the effects of alteration of glycan structures on the function of glycoproteins and cell phenotypes, the basic technologies for the following purposes are necessary.(1) Glycogenes:The human-derived glycogenes were comprehensively identified and analyzed in the project for establishment of a glycogene library, Glycogene (GG) Project. To synthesize a glycoprotein, the protein moiety is regulated by expression of one gene, but the glycan moiety is controlled by the coordinate expression of dozens of glycogenes. Therefore, if all the glycogenes are elucidated, the mechanisms for biological synthesis of glycoproteins and glycolipids should be clarified. To reach the final goal, that is, understanding of the glycan functions, elucidation of all glycogenes was necessary as

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