Wo! Where did this come from? Did this "delgijer" create this, or is this a cut and paste from somewhere?? Interesting...... I was going to also start to use "substrate deprivation" as a rallying thought.......
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Huge market
by: delgijer 12/10/02 11:46 am
Msg: 59 of 60
Protein and lipid-linked oligosaccharides are a large component of the eukaryotic cell surface where they play important roles in cell-cell and cell-pathogen interactions and adhesion. Alterations in both the synthesis or catabolism of these oligosaccharides have serious and life threatening consequences, such as tumour metastasis, carbohydrate deficiency syndromes and lysosomal storage diseases.
The experimental manipulation of oligosaccharide biosynthesis by the use of enzyme specific inhibitors has proved useful in understanding the functional roles of protein-linked oligosaccharides. When the early stages of oligosaccharide maturation are blocked with alpha-glucosidase inhibitors, such as N-butyl-deoxynojirimycin, many glycoproteins fail to undergo chaperone-mediated protein folding, leading to an altered conformation and loss of biological activity. This discovery has lead to the exploitation of processing inhibitors as anti-viral (HIV and Hepatitis B) therapeutics. (Collaborator: Professor Timothy Block, Jefferson Medical College, USA). In addition to being potent glycosidase inhibitors, certain members of the deoxynojirimycin family of sugar mimics act as a ceramide specific glucosyltransferase inhibitors. The glucosyltransferase is a key enzyme in the pathway for the synthesis of the lactosyl-, and globosyl-ceramide series, and gangliosides. In cells and in vivo, inhibitor treatment can prevent the synthesis of most glycosphingolipids and therefore provide model systems for understanding glycolipid biology. (Collaborators: Dr Tom Seyfried, Boston College, USA; Professor Tim Mitchell,Glasgow University; Dr Catharina Svanborg, University-Lund, Sweden). Study of the glucosyltransferase/inhibitor interactions enables further definition of glycolipid trafficking in the cell and dissection at the molecular level permits better inhibitor design. (Collaborators: Professor Yoshio Hirabayashi, RIKEN, Tokyo, Japan; Dr George Fleet, Dyson Perrins Laboratory, University of Oxford).
The use of these novel glycolipid inhibitors allows evaluation of a ‘substrate deprivation strategy’ for the treatment of human glycosphingolipid lysosomal storage diseases. A reduction in the level of newly synthesised glycolipids allows the partially active lysosomal enzyme present in these disease states to catabolise the stored products preventing the associated pathology. Mouse knockout models for several of the human diseases are being assessed for therapeutic efficacy that will provide the basis for human trials. (Collaborators: Professor Hugh Perry, Southampton University; Dr Rick Proia and Dr Ashok Kulkarni, NIH, Bethesda, USA; Professor Bryan Winchester, ICH, London; Dr Ashok Velodi, Great Ormond St Hospital, London; Professor Timothy Cox, University of Cambridge).
(damn, and I had weaned myself down to only three or four threads at Yahoo!) |
