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Conformational Behaviour of Azasugars Based on Mannuronic Acid

DOI: 10.1002/cbic.201700080 DOI Help

Authors: Erwin R. Van Rijssel (Leiden University) , Antonius P. A. Janssen (Leiden University) , Alexandra Males (The University of York) , Gideon J. Davies (University of York) , Gijsbert A. Van Der Marel (Leiden University) , Herman S. Overkleeft (Leiden University) , Jeroen D. C. Codée (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chembiochem , VOL 4

State: Published (Approved)
Published: April 2017
Diamond Proposal Number(s): 9948

Open Access Open Access

Abstract: A set of mannuronic-acid-based iminosugars, consisting of the C-5-carboxylic acid, methyl ester and amide analogues of 1deoxymannorjirimicin (DMJ), was synthesised and their pH-dependent conformational behaviour was studied. Under acidic conditions the methyl ester and the carboxylic acid adopted an “inverted” 1C4 chair conformation as opposed to the “normal” 4C1 chair at basic pH. This conformational change is explained in terms of the stereoelectronic effects of the ring substituents and it parallels the behaviour of the mannuronic acid ester oxocarbenium ion. Because of this solution-phase behaviour, the mannuronic acid ester azasugar was examined as an inhibitor for a Caulobacter GH47 mannosidase that hydrolyses its substrates by way of a reaction itinerary that proceeds through a 3H4 transition state. No binding was observed for the mannuronic acid ester azasugar, but sub-atomic resolution data were obtained for the DMJ⋅CkGH47 complex, showing two conformations—3S1 and 1C4—for the DMJ inhibitor.

Journal Keywords: azasugars; conformation analysis; inhibitor design; mannosidases; stereoelectronic effects

Subject Areas: Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
van-Rijssel_et_al-2017-ChemBioChem.pdf