Functional analysis of glycosaminoglycans as a potential drug target and the decoding of carbohydrate signaling of the functional domains

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We isolated for the first time non-sulfated chondroitn, which is a potential drug target, from Hydra. However, it was also found that hyaluronan was not synthesized in Hydra as reported for nematode (C. elegans). Previously, we reported that chondroitin plays critical roles in cytokinesis and cell division in C. elegans (Mizuguchi et al., Nature 2003). Here we identified a chondroitin hydrolase in C. elegans (filed for patent). These results may lead to a discovery of a novel function of chondroitin in Hydra, which has a nervous system. In addition, non-sulfated chondroitin was demonstrated in bird's nest, which has also a potential therapeutic application.On the other hand, hepatocyte growth factor (HGF) was identified as a regulatory molecule involved in the neurite outgrowth promoting activity of chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains derived from pig brain. Furthermore, it was demonstrated that the molecular mechanisms of such activity involve the signal transduction of HGF and pleiotrophin. In addition, CS/DS hybrid chains, which showed the neurite outgrowth promoting activity, were also found in shark liver but also in king crab cartilage. A novel, sensitive, and non-destructive 1D ^1H-NMR-based method was developed to determine the proportion of iduronic acid and glucuronic acid residues in CS/DS hybrid chains.The sugar sequences of the CS epitopes drecognized by several antibodies, powerful tools of the functional analysis of CS, were determinded. Furthermore, the molecular shape and the distribution of the electrostatic potential were demonstrated to be critical in the sugar recognition by the antibodies. A part of these results was recently reviewed (Sugahara K., and Mikami T., Curr. Opin. Struct. Biol., 2007).