title: Conformational Behaviour of Azasugars Based on Mannuronic Acid.
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"1C4chair conformation as opposed to the "normal"4C1chair 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 a3H4transition 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-3S1and1C4-for the DMJ inhibitor.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Erwin R
authors.initials: ER
authors.lastname: van Rijssel
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Antonius P A
authors.initials: APA
authors.lastname: Janssen
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, The University of York, York, YO10 5DD, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Males
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, The University of York, York, YO10 5DD, UK.
authors.forename: Gideon J
authors.initials: GJ
authors.lastname: Davies
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Jeroen D C
authors.identifier: 0000-0003-3531-2138
authors.initials: JDC
authors.lastname: Codée
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002264:Carboxylic Acids / Q000737:chemistry*; D016934:Caulobacter / Q000737:chemistry / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D004952:Esters / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry*; D008361:Mannosidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular
chemical_list: D001372:Aza Compounds; D001426:Bacterial Proteins; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D004952:Esters; D006603:Hexuronic Acids; D050111:Imino Sugars; C008324:mannuronic acid; D008361:Mannosidases
keywords: azasugars; conformation analysis; inhibitor design; mannosidases; stereoelectronic effects