Anti-Blood Group N antigen monoclonal antibody

The human ABO(H) blood group A- and B-synthesizing glycosyltransferases GTA and GTB have been structurally characterized to high resolution in complex with their respective trisaccharide antigen products. These findings are particularly timely and relevant given the dearth of glycosyltransferase structures collected in complex with their saccharide reaction products. GTA and GTB utilize the same acceptor substrates, oligosaccharides terminating with alpha-l-Fucp-(1 -> 2)-beta-d-Galp-OR (where R is a glycolipid or glycoprotein), but use distinct UDP donor sugars, UDP-N-acetylgalactosamine and UDP-galactose, to generate the blood group A (alpha-l-Fucp-(1 -> 2)[alpha-d-GalNAcp-(1 -> 3)]-beta-d-Galp-OR) and blood group B (alpha-l-Fucp-(1 -> 2)[alpha-d-Galp-(1 -> 3)]-beta-d-Galp-OR) determinant structures, respectively. Structures of GTA and GTB in complex with their respective trisaccharide products reveal a conflict between the transferred sugar monosaccharide and the beta-phosphate of the UDP donor. Mapping of the binding epitopes by saturation transfer difference NMR measurements yielded data consistent with the X-ray structural results. Taken together these data suggest a mechanism of product release where monosaccharide transfer to the H-antigen acceptor induces active site disorder and ejection of the UDP leaving group prior to trisaccharide egress.

Glycans are essential biomolecules in regulating human physiology and pathology ranging from signal transduction to microbial infections. Developing complex human diseases, such as cancer, diabetes, and cardiovascular diseases, are a combination of genetic and environmental factors. Genetics dominates embryonic development and the passing of genes to the next generation whereas the information in glycans reflects the impact of internal and external environmental factors, such as diseases, lifestyle, and social factors, on a person's health and disease. The reason behind this is that glycans are not directly encoded in a genetic template. Instead, they are assembled dynamically by hundreds of enzymes organized in more than 10 complex biosynthetic pathways. Any environmental changes affecting enzymatic activities or the availability of high-energy monosaccharide donors in a specific location will disturb the final structure of glycans. The glycan structure-dependent biological activities subsequently enable or disable gene expressions, which partially explain that it is difficult to pinpoint specific genetic defects to aging-associated diseases. Glycan-based biomarkers are currently used for diagnosis of diabetes, cancers, and other complex diseases. We will recapitulate the discovery of glucose, glycated proteins, glycan-, and glycoprotein-based biomarkers followed by summarizing clinically used glycan/glycoprotein-based biomarkers. The potential serum/plasma-derived N- and O-linked glycans as biomarkers will also be discussed.