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Development of Non-Hydrolysable Oligosaccharide Activity-Based Inactivators for Endoglycanases: A Case Study on alpha-1,6 Mannanases
- Source :
- CHEM-EUR J, 27(37), 9519-9523. WILEY-V C H VERLAG GMBH, Schröder, S P, Offen, W A, Males, A, Jin, Y, Boer, C, Enotarpi, J, Marino, L, Marel, G A, Florea, B I, Codée, J D C, Overkleeft, H S & Davies, G J 2021, ' Development of Non-Hydrolysable Oligosaccharide Activity-Based Inactivators for Endoglycanases: A Case Study on alpha-1,6 Mannanases ', Chemistry – A European Journal, vol. 27, no. 37, pp. 9519-9523 . https://doi.org/10.1002/chem.202101255, Chemistry (Weinheim an Der Bergstrasse, Germany)
- Publication Year :
- 2021
-
Abstract
- There is a vast genomic resource for enzymes active on carbohydrates. Lagging far behind, however, are functional chemical tools for the rapid characterization of carbohydrate‐active enzymes. Activity‐based probes (ABPs) offer one chemical solution to these issues with ABPs based upon cyclophellitol epoxide and aziridine covalent and irreversible inhibitors representing a potent and widespread approach. Such inhibitors for enzymes active on polysaccharides are potentially limited by the requirement for several glycosidic bonds, themselves substrates for the enzyme targets. Here, it is shown that non‐hydrolysable trisaccharide can be synthesized and applied even to enzymes with challenging subsite requirements. It was found that incorporation of carbasugar moieties, which was accomplished by cuprate‐assisted regioselective trans‐diaxial epoxide opening of carba‐mannal synthesised for this purpose, yields inactivators that act as powerful activity‐based inhibitors for α‐1,6 endo‐mannanases. 3‐D structures at 1.35–1.47 Å resolutions confirm the design rationale and binding to the enzymatic nucleophile. Carbasugar oligosaccharide cyclophellitols offer a powerful new approach for the design of robust endoglycosidase inhibitors, while the synthesis procedures presented here should allow adaptation towards activity‐based endoglycosidase probes as well as configurational isosteres targeting other endoglycosidase families.<br />Carba‐trisaccharide cyclophellitols are potent GH76 α‐1,6 endo‐mannanase inactivators and resistant to endoglycosidic bond cleavage.
- Subjects :
- Glycoside Hydrolases
Stereochemistry
polysaccharides
Oligosaccharides
010402 general chemistry
01 natural sciences
Catalysis
Endoglycosidase
chemistry.chemical_compound
Trisaccharide
endoglycosidase
chemistry.chemical_classification
biology
010405 organic chemistry
Communication
Organic Chemistry
Regioselectivity
Glycosidic bond
General Chemistry
Carbasugars
Aziridine
Oligosaccharide
Communications
0104 chemical sciences
Carbasugar
mechanism-based inhibitor
Enzyme
chemistry
Covalent bond
cyclophellitol
biology.protein
Epoxy Compounds
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- CHEM-EUR J, 27(37), 9519-9523. WILEY-V C H VERLAG GMBH, Schröder, S P, Offen, W A, Males, A, Jin, Y, Boer, C, Enotarpi, J, Marino, L, Marel, G A, Florea, B I, Codée, J D C, Overkleeft, H S & Davies, G J 2021, ' Development of Non-Hydrolysable Oligosaccharide Activity-Based Inactivators for Endoglycanases: A Case Study on alpha-1,6 Mannanases ', Chemistry – A European Journal, vol. 27, no. 37, pp. 9519-9523 . https://doi.org/10.1002/chem.202101255, Chemistry (Weinheim an Der Bergstrasse, Germany)
- Accession number :
- edsair.doi.dedup.....503a40aafc1803d748abf9432d41357f