WO2008002230A1 - Production of glycoside oligosaccharides - Google Patents
Production of glycoside oligosaccharides Download PDFInfo
- Publication number
- WO2008002230A1 WO2008002230A1 PCT/SE2007/000209 SE2007000209W WO2008002230A1 WO 2008002230 A1 WO2008002230 A1 WO 2008002230A1 SE 2007000209 W SE2007000209 W SE 2007000209W WO 2008002230 A1 WO2008002230 A1 WO 2008002230A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glycoside
- glycosides
- production
- lactose
- metabolically engineered
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/64—Preparation of S-glycosides, e.g. lincomycin
Definitions
- the present invention involves products produced using metabolically engineered bacteria or cells.
- Metabolically engineered cells are used in common practice to produce oligosaccharides found in glycoproteins and glycolipids, see for example Angewandte Chemie, International Ed., 2006, 45, 1778-1780.
- milk oligosaccharides blood group determinants, e.g. A, B, Lewis structures etc, and oligosaccharides found in gangliosides, may be produced.
- lactose is used as the first acceptor saccharide, and a ⁇ -galactoside permease is transferring the lactose into the metabolically engineered cell. In this way oligosaccharides terminating in lactose, e.g. of the types described above can be produced.
- This invention describes the production of glycosides of e.g. the above mentioned types of oligosaccharides. This is achieved according to the invention by instead of lactose using a glycoside of lactose as the initial acceptor molecule.
- an -O-, -N- or -S- ⁇ - or ⁇ -glycoside of lactose is used according to the invention as the initial acceptor molecule for production of an -O-, -N- or -S,- ⁇ - or ⁇ -glycoside of e.g. above mentioned oligosaccharides, using metabolically engineered bacteria.
- - ⁇ - or ⁇ -glycoside of lactose i.e. Gal ⁇ l-4Glc ⁇ -OR, or Gal ⁇ l-4Glc ⁇ -OR, where R is an aliphatic or aromatic organic molecule
- R is an aliphatic or aromatic organic molecule
- Gal ⁇ l-4Glc ⁇ -NH-R or Gal ⁇ l-4Glc ⁇ -N(Ac)-R where R is an aliphatic or aromatic molecule
- R' is for example an acyl group containing organic compound
- R' is an -CO-CF3 group.
- -O-, -N- or -S,- ⁇ - or ⁇ -glycoside of other types of saccharides can be used as the initial acceptor molecule according to the invention.
- -O-, -N- or -S,- ⁇ - or ⁇ -glycosides of mono-, di-, tri- or higher saccharides may be used according to the invention.
- the mono-, di-, tri- or higher oligosaccharide may contain one or more of the monosaccharides galactose, glucose, N-acetylgalactosamine, N- acetylglucosamine, N-acetylmannosamine, fucose, mannose or xylose.
- the glycoside may also in its R-group contain one or more amino acid, peptide or other molecule of biological activity.
- the metabolically engineered cell may contain one or more glycosyltransferase, such as one or more of a fucosyl-, galactosyl-, mannosyl-, sialyl-, N-acetylgalactosaminyl- or a N- acetylglucosaminyltransferase.
- the metabolically engineered cell may also contain genes expressing enzymes in the metabolically engineered cell for the production of one or more of the nucleotide sugars required as glycosyl donors and used by one or more of the glycosyltransferases, e.g. genes for synthesis of GDP-Fuc, CMP-Neu5Ac, UDP-GIc, UDP- GaI, UDP-GIcNAc, UDP-GaINAc or other suitable nucleotide sugar.
- the construction of the desired metabolically engineered cells and/or bacteria for example the introduction of glycosyltransferase genes, the introduction of genes for synthesis of nucleotide sugars into cells or bacteria, isolation of produced oligosaccharide glycosides e.g. with principles based on chromatography, are performed by the expert in the field and does not limit the scope of the invention.
- the invention also relates to the isolation of produced oligosaccharide glycosides using a hydrophobic resin for isolation.
- Previously produced sugars were isolated by preferentially separation based on size, but this can be achieved more efficiently when glycosides are produced, especially when hydrophobic aglycon glycosides are produced, using hydrophobic resins, such as C18-silica, which binds hydrophobic aglycon glycosides.
- the invention also relates to the saccharide oligosaccharide glycoside products obtained using metabolically engineered cells and the glycosides or lactose-glycosides as initial acceptors described above, as obtained after further purification of the product with ultrafiltration to for example remove or reduce the endotoxin content of the product.
- Examples of preferential sugars produced according to the invention are: Blood group A glycosides, Blood group B glycosides and GMl glycosides.
- Non-limiting examples of Blood group A glycosides and related glycosides according to the invention and produced according to the invention are
- Non-limiting examples of Blood group B glycosides according to the invention and produced according to the invention are
- Non-limiting examples of GMl glycosides are
- N-glycosides may be produced as described above. This results in according to the invention, the production of glycosides of e.g. the above mentioned types of oligosaccharides.
- these products can be used for further modification, e.g. after modification of the aglycon part of the produced oligosaccharide glycoside, or without prior modification, for example if the aglycon of the oligosaccharide glycoside contains an amino group, can be used for example, for coupling to mono-, di or oligomeric substances, e.g. peptides, oligosaccharides, proteins or separation materials, biosensor surfaces, bioarray chips, nanoparticles or ELISA plates.
- mono-, di or oligomeric substances e.g. peptides, oligosaccharides, proteins or separation materials, biosensor surfaces, bioarray chips, nanoparticles or ELISA plates.
- oligosaccharide materials can be used for example specific detection or determination of oligosaccharide proteins or antibodies, or for reduction of or for removal of for example proteins or antibodies e.g. anti-A or anti-B or anti-GMl antibodies, from for example human blood or from other material.
- the blood group A or B or GMl glycosides exemplified above can be converted to contain an aglycon containing an amino group.
- aglycons can before or after isolation of the produced oligosaccharide glycoside, be converted by addition, ozonolysis or oxidation (allyl), -O(CH2)riNH2 (by hydrolysis), -O(CH2)nPhNH2 (by hydrogenation), or -O(CH2)nPhNH2 (by hydrolysis).
- the resulting blood group A or B or GMl amino group containing glycosides can then, or after purification by standard methods or after purification also involving ultrafiltration to reduce or remove endotoxins, be coupled to another compound or material such as e.g. a peptide, another di-, oligo- or polymeric material, a protein, a biosensor surface, a separation material, nanoparticles, ELISA plates or or bioarray chip and used as described above.
- Another compound or material such as e.g. a peptide, another di-, oligo- or polymeric material, a protein, a biosensor surface, a separation material, nanoparticles, ELISA plates or or bioarray chip and used as described above.
- Matrix can be for example agarose or Sepharose, or another separation material
- n and m is an integer preferentially, 1, 2, 3 or 4.
Abstract
Product and products obtained using metabolically engineered bacteria or cell and lactose or other glycoside as initial acceptor for production of tri- and/or higher oligosaccharide glycosides.
Description
Product and production
The present invention involves products produced using metabolically engineered bacteria or cells.
Metabolically engineered cells are used in common practice to produce oligosaccharides found in glycoproteins and glycolipids, see for example Angewandte Chemie, International Ed., 2006, 45, 1778-1780. Thus, as non-limiting examples milk oligosaccharides, blood group determinants, e.g. A, B, Lewis structures etc, and oligosaccharides found in gangliosides, may be produced.
Often lactose is used as the first acceptor saccharide, and a β-galactoside permease is transferring the lactose into the metabolically engineered cell. In this way oligosaccharides terminating in lactose, e.g. of the types described above can be produced.
This invention describes the production of glycosides of e.g. the above mentioned types of oligosaccharides. This is achieved according to the invention by instead of lactose using a glycoside of lactose as the initial acceptor molecule.
Thus, an -O-, -N- or -S-α- or β-glycoside of lactose is used according to the invention as the initial acceptor molecule for production of an -O-, -N- or -S,-α- or β-glycoside of e.g. above mentioned oligosaccharides, using metabolically engineered bacteria.
Thus, for example -α- or β-glycoside of lactose, i.e. Galβl-4Glcα-OR, or Galβl-4Glcβ-OR, where R is an aliphatic or aromatic organic molecule, or for example Galβl-4Glcβ-NH-R or Galβl-4Glcβ -N(Ac)-R, where R is an aliphatic or aromatic molecule, is used as the initial acceptor molecule for the glycosyltransferase reactions in the metabolically engineered cell.
Non-limiting examples of R is for example -allyl, -propargyl, -(CH2)nCOOMe, -(CH2)nNH-R'5 -(CH2)nPhNO2, -(CH2)nPhNH-R'5 where n is an integer, preferentially n = either one of 1, 2, 3, 4, 5, or 6, and R' is for example an acyl group containing organic compound, one non-limiting example of R' is an -CO-CF3 group.
According to the invention, also -O-, -N- or -S,-α- or β-glycoside of other types of saccharides can be used as the initial acceptor molecule according to the invention. Thus, for example -O-, -N- or -S,-α- or β-glycosides of mono-, di-, tri- or higher saccharides may be used according to the invention. The mono-, di-, tri- or higher oligosaccharide may contain one or more of the monosaccharides galactose, glucose, N-acetylgalactosamine, N- acetylglucosamine, N-acetylmannosamine, fucose, mannose or xylose. The glycoside may also in its R-group contain one or more amino acid, peptide or other molecule of biological activity.
The metabolically engineered cell may contain one or more glycosyltransferase, such as one or more of a fucosyl-, galactosyl-, mannosyl-, sialyl-, N-acetylgalactosaminyl- or a N- acetylglucosaminyltransferase. The metabolically engineered cell may also contain genes expressing enzymes in the metabolically engineered cell for the production of one or more of the nucleotide sugars required as glycosyl donors and used by one or more of the glycosyltransferases, e.g. genes for synthesis of GDP-Fuc, CMP-Neu5Ac, UDP-GIc, UDP- GaI, UDP-GIcNAc, UDP-GaINAc or other suitable nucleotide sugar.
The construction of the desired metabolically engineered cells and/or bacteria, for example the introduction of glycosyltransferase genes, the introduction of genes for synthesis of nucleotide sugars into cells or bacteria, isolation of produced oligosaccharide glycosides e.g. with principles based on chromatography, are performed by the expert in the field and does not limit the scope of the invention.
Also, the practical use of metabolically engineered cells for production of different carbohydrate structures, the addition of reagents, the fermentation reaction with suitable conditions for the metabolically engineered cells or bacteria to produce desired oligosaccharide glycosides and to optimize the reaction conditions to optimize the yields of the desired product are performed by the expert in the field and do not limit the scope of the present invention.
The invention also relates to the isolation of produced oligosaccharide glycosides using a hydrophobic resin for isolation. Previously produced sugars were isolated by preferentially separation based on size, but this can be achieved more efficiently when glycosides are
produced, especially when hydrophobic aglycon glycosides are produced, using hydrophobic resins, such as C18-silica, which binds hydrophobic aglycon glycosides.
The invention also relates to the saccharide oligosaccharide glycoside products obtained using metabolically engineered cells and the glycosides or lactose-glycosides as initial acceptors described above, as obtained after further purification of the product with ultrafiltration to for example remove or reduce the endotoxin content of the product.
Examples of preferential sugars produced according to the invention are: Blood group A glycosides, Blood group B glycosides and GMl glycosides.
Non-limiting examples of Blood group A glycosides and related glycosides according to the invention and produced according to the invention are
GalNAcαl-3(Fucαl-2)Galβl-4Glcβ-OR,
GalNAcαl-3(Fucαl-2)Galβl-3GlcNAcβl-3Galβl-4Glcβ-OR
GalNAcαl-3Galβl-4Glcβ-OR
GalNAcαl-3Galβl-3GlcNAcβl-3Galβl-4Glcβ-OR and the precursor substance
Galβl-3GlcNAcβl-3Galβl-4Glcβ-OR
Non-limiting examples of Blood group B glycosides according to the invention and produced according to the invention are
Galαl-3(Fucαl-2)Galβl-4Glcβ-OR,
Galαl -3(Fucαl -2)Galβ l-3GlcNAcβ 1 -3Galβ 1 -4Glcβ-OR
Galαl -3 Galβ 1 -4Glcβ-OR
Galαl-3Galβl-3GlcNAcβl-3Galβl-4Glcβ-OR
Non-limiting examples of GMl glycosides are
Galβ 1 -3 GalNAcβ 1 -3 (Neu5NAcα2-3)Galβ 1 -4Glcβ-OR
where R is an aliphatic or aromatic organic molecule as described above, also instead of O- glycosides, N-glycosides may be produced as described above.
This results in according to the invention, the production of glycosides of e.g. the above mentioned types of oligosaccharides.
After isolation, these products can be used for further modification, e.g. after modification of the aglycon part of the produced oligosaccharide glycoside, or without prior modification, for example if the aglycon of the oligosaccharide glycoside contains an amino group, can be used for example, for coupling to mono-, di or oligomeric substances, e.g. peptides, oligosaccharides, proteins or separation materials, biosensor surfaces, bioarray chips, nanoparticles or ELISA plates.
The present invention also relates to such products and their use. Thus produced oligosaccharide materials can be used for example specific detection or determination of oligosaccharide proteins or antibodies, or for reduction of or for removal of for example proteins or antibodies e.g. anti-A or anti-B or anti-GMl antibodies, from for example human blood or from other material.
Thus, for example, the blood group A or B or GMl glycosides exemplified above can be converted to contain an aglycon containing an amino group.
Thus, for example -OR in the produced, according to the invention, blood group A, B or GMl structures exemplified above, can be one of for example -OCH2CH=CH2 (allyl), -O(CH2)nNH-R', -O(CH2)nPhNO2, or -O(CH2)nPhNH-R.
These aglycons can before or after isolation of the produced oligosaccharide glycoside, be converted by addition, ozonolysis or oxidation (allyl), -O(CH2)riNH2 (by hydrolysis), -O(CH2)nPhNH2 (by hydrogenation), or -O(CH2)nPhNH2 (by hydrolysis).
For example, the resulting blood group A or B or GMl amino group containing glycosides can then, or after purification by standard methods or after purification also involving ultrafiltration to reduce or remove endotoxins, be coupled to another compound or material such as e.g. a peptide, another di-, oligo- or polymeric material, a protein, a biosensor surface, a separation material, nanoparticles, ELISA plates or or bioarray chip and used as described above.
One example is coupling of the amino-group containing blood group A or B or GMl structure to N-hydrosuccinimido-containing molecule or material, for example N-hydroxysuccinimide activated C=O group containing material or Matrix. This results in the covalent coupling of the amino group containing blood group A or B or GMl structure forming a NH-CO bond.
Non-limiting examples of thus generated compounds are
Blood group A-O(CH2)HPhNH-CO-(CH2)J31NH-CH2-CH(OH)-CH2-O-MaMx
Blood group B-O(CH2)nPhNH-CO-(CH2)mNH-CH2-CH(OH)-CH2-0-Matrix GMl-O(CH2)nPhNH-CO-(CH2)mNH-CH2-CH(OH)-CH2-O-Matrix
Where blood group A, B and GMl structures have been exemplified above and Matrix can be for example agarose or Sepharose, or another separation material, n and m is an integer preferentially, 1, 2, 3 or 4.
Claims
1. Product and products obtained using metabolically engineered bacteria or cell and lactose or other glycoside as initial acceptor for production of tri- and/or higher oligosaccharide glycosides.
2. Product and products according to claim 1, where the product is related to blood group A glycoside, blood group B glycoside or GMl glycoside, and characterized by that at least one reaction to produce said glycoside uses metabolically engineered bacteria or cell containing at least one glycosyltransferase, and where lactose glycoside is used as initial acceptor for production of said saccharide glycosides.
3. Product and products according to claim 1 and 2, and products obtained therefrom and their use.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0600602 | 2006-03-04 | ||
| SE0600602-7 | 2006-03-04 | ||
| SE0700373-4 | 2007-02-08 | ||
| SE0700373 | 2007-02-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008002230A1 true WO2008002230A1 (en) | 2008-01-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE2007/000209 WO2008002230A1 (en) | 2006-03-04 | 2007-03-04 | Production of glycoside oligosaccharides |
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| WO (1) | WO2008002230A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013091660A1 (en) * | 2011-12-23 | 2013-06-27 | Glycom A/S | A method for obtaining crystalline lacto-n-tetraose and lacto-n-neotetraose precursors and mixtures thereof |
| WO2013182206A1 (en) * | 2012-06-08 | 2013-12-12 | Glycom A/S | Method for producing oligosaccharides and oligosaccharide glycosides by fermentation |
| WO2014048439A1 (en) * | 2012-09-25 | 2014-04-03 | Glycom A/S | Glycoconjugate synthesis |
| EP2823821A1 (en) | 2009-07-06 | 2015-01-14 | F. Hoffmann-La Roche AG | Antibody specifically binding to digoxigenin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000012747A1 (en) * | 1998-08-31 | 2000-03-09 | Kurt Nilsson | Method for enzymatic synthesis of glycosides, disaccharides, and oligosaccharides |
| FR2796082A1 (en) * | 1999-07-07 | 2001-01-12 | Centre Nat Rech Scient | OLIGOSACCHARIDES PRODUCTION PROCESS |
-
2007
- 2007-03-04 WO PCT/SE2007/000209 patent/WO2008002230A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000012747A1 (en) * | 1998-08-31 | 2000-03-09 | Kurt Nilsson | Method for enzymatic synthesis of glycosides, disaccharides, and oligosaccharides |
| FR2796082A1 (en) * | 1999-07-07 | 2001-01-12 | Centre Nat Rech Scient | OLIGOSACCHARIDES PRODUCTION PROCESS |
Non-Patent Citations (2)
| Title |
|---|
| ABERG P.-M. ET AL.: "Large scale synthesis of two trisaccharide spacer glycosides corresponding to the blood group A and B determinants using thioglycosides and dimethyl(thiomethyl)sulfonium tetrafluoroborate (DMTSB) as promoter", JOURNAL OF CARBOHYRATE CHEMISTRY, vol. 13, no. 2, 1994, pages 141 - 161, XP009000010 * |
| MONG TONY KWOK-KONG ET AL.: "Reactivity-based one-pot total synthesis of fucose GM1 oligosaccharide: A sialylated antigenic epitope of small-cell lung cancer", PROCEEDINGS OF THE NATIONAL ACADMEY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 100, no. 3, 2003, pages 797 - 802, XP003020354 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2823821A1 (en) | 2009-07-06 | 2015-01-14 | F. Hoffmann-La Roche AG | Antibody specifically binding to digoxigenin |
| WO2013091660A1 (en) * | 2011-12-23 | 2013-06-27 | Glycom A/S | A method for obtaining crystalline lacto-n-tetraose and lacto-n-neotetraose precursors and mixtures thereof |
| WO2013182206A1 (en) * | 2012-06-08 | 2013-12-12 | Glycom A/S | Method for producing oligosaccharides and oligosaccharide glycosides by fermentation |
| WO2014048439A1 (en) * | 2012-09-25 | 2014-04-03 | Glycom A/S | Glycoconjugate synthesis |
| EP2900829A4 (en) * | 2012-09-25 | 2016-03-02 | Glycom As | Glycoconjugate synthesis |
| US9816122B2 (en) | 2012-09-25 | 2017-11-14 | Glycom A/S | Glycoconjugate synthesis |
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