Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Patent
1992-02-18
1994-12-13
Griffin, Ronald W.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
435100, 435101, 435200, 536 41, 536 174, 536 176, C12P 1904, C12P 1912, C12N 922, C07H 306
Patent
active
053729374
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method for enzymatic synthesis of an oligosaccharide compound, which either consists of or is a fragment or an analog of the carbohydrate part in a glycoconjugate. Furthermore, the invention relates to the use of the product prepared by this method.
It has been found that the oligosaccharide part of various glycoconjugates (especially glycolipids and glycoproteins) have a number of important functions in vivo (Biology of Carbohydrates, vol. 2, Ginsburg et al., Wiley, N.Y., 1984; The Glycoconjugates, vol. I-V, Academic Press, New York; S. Hakomori, Ann. Rev. Biochem., vol. 50, pp. 733-64); Feizi, Nature, pp. 314, 1985; S. Hakomori, Chemistry and Physics of Lipids, vol 42, pp. 209-33). Among other things it was found that localisation, immunogenicity and degradation of glycoproteins; antigens); pathogens, proteins, hormones, toxins and during cell-cell interactions; oligosaccharides have been found to be cancer-associated antigenic determinants; carbohydrate part of the glycoconjugate is required for full biological activity (e.g. receptor activity).
Universities and Industry are at present working intensely on developing the use of biologically active oligosaccharides within a number of different fields, such as based on the inhibition of the attachment of bacteria and virus on cell surfaces with specific oligosaccharides
Besides the above mentioned areas, a considerable future market is envisaged for fine chemicals based on biologically active carbohydrates.
About ten different monosaccharides are included in the carbohydrate part of the glycoconjugates: D-glucose (Glc), D-galactose (Gal), N-acetyl-D-glucosamine (GlcNAc), N-acetyl-neuraminic acid (Neu5Ac), D-mannose (Man), L-fucose (Fuc), N-acetyl-D-galactosamin (GalNAc), xylose (Xyl) and arabinose (Ara) (the abbreviations in brackets are according to IUPAC-IUB's abridged terminology for monosaccharides, J.Biol.Chem., vol 257, pp. 3347-3354, 1982, in which publication one also can find the nomenclature used in this text to describe oligosaccharide sequences). The number of possible structures will be almost infinitely great because both the anomeric configuration and the position of the O-glycosidic bond can be varied.
The organic chemical techniques used today for synthesis of these carbohydrate structures require an extensive protective group chemistry with many steps of synthesis and expensive catalysts. Low total yields are obtained in these complicated reaction schemes and the techniques is not favorable, especially for larger scale work.
Enzymes are nature's own catalysts with many attractive characteristics, such as high stereo-, regio-, and substrate selectively as well as high catalytic activity under mild conditions. Today, great hopes are therefore placed in being able to utilise enzymes for large-scale selective synthesis of oligosaccharides with fewer reaction steps and consequently higher total yields than by organic chemical methodology.
Both hydrolases (glycosidases, EC 3.2) and glycosyltransferases (EC 2.4) can be used for synthesis (glycosidases: see Nisizawa et al, in "The Carbohydrates, Chemistry and Biochemistry", 2nd ed., vol IIA, pp. 242-290, Academic Press, New York, 1970). With glycosidases reversed hydrolysis (equilibrium reaction) or transglycosylation (kinetic reaction) are often used to obtain synthesis (see e.g. K.G.I. Nilsson, Carbohydr. Res., vol. 167, pp. 95-103, 1987, Trends in Biotechnology., vol. 6, 256-264, 1988). ##STR1## (DOH is donor saccharide, DOR is donor glycoside with .alpha.- or .beta.-glycosidically bound aglycon (=R), HOA is acceptor saccharide and EH is enzyme)
With transferases, a nucleotide sugar (UDP-Gal, CMP-Sia, UDP-GalNAc, GDP-Fuc, etc), which is relatively expensive, is used as donor. Furthermore, glycosidases are abundant and can often be used directly without purification. A disadvantage is however that relatively low yields and the wrong product isomers often are obtained. Thus, preponderant formation of 1-6-linkages (i.e. linkages to the primary hydroxyl group of
REFERENCES:
patent: 4918009 (1990-04-01), Nilsson
Paulson et al., Journal of Biological Chemistry, 253(16); pp. 5617-5624 (1978).
Griffin Ronald W.
Procur Aktiebolag
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