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dc.contributor.authorFernandes, PZ
dc.contributor.authorPetricevic, M
dc.contributor.authorSobala, L
dc.contributor.authorDavies, GJ
dc.contributor.authorWilliams, SJ
dc.date.accessioned2020-12-18T04:14:36Z
dc.date.available2020-12-18T04:14:36Z
dc.date.issued2018-05-23
dc.identifier.citationFernandes, P. Z., Petricevic, M., Sobala, L., Davies, G. J. & Williams, S. J. (2018). Exploration of Strategies for Mechanism-Based Inhibitor Design for Family GH99 endo--1,2-Mannanases. CHEMISTRY-A EUROPEAN JOURNAL, 24 (29), pp.7464-7473. https://doi.org/10.1002/chem.201800435.
dc.identifier.issn0947-6539
dc.identifier.urihttp://hdl.handle.net/11343/256111
dc.description.abstractendo-α-1,2-Mannosidases and -mannanases, members of glycoside hydrolase family 99 (GH99), cleave α-Glc/Man-1,3-α-Man-OR structures within mammalian N-linked glycans and fungal α-mannan, respectively. They are proposed to act through a two-step mechanism involving a 1,2-anhydrosugar "epoxide" intermediate incorporating two conserved catalytic carboxylates. In the first step, one carboxylate acts as a general base to deprotonate the 2-hydroxy group adjacent to the fissile glycosidic bond, and the other provides general acid assistance to the departure of the aglycon. We report herein the synthesis of two inhibitors designed to interact with either the general base (α-mannosyl-1,3-(2-aminodeoxymannojirimycin), Man2NH2 DMJ) or the general acid (α-mannosyl-1,3-mannoimidazole, ManManIm). Modest affinities were observed for an endo-α-1,2-mannanase from Bacteroides thetaiotaomicron. Structural studies revealed that Man2NH2 DMJ binds like other iminosugar inhibitors, which suggests that the poor inhibition shown by this compound is not a result of a failure to achieve the expected interaction with the general base, but rather the reduction in basicity of the endocyclic nitrogen caused by introduction of a vicinal, protonated amine at C2. ManManIm binds with the imidazole headgroup distorted downwards, a result of an unfavourable interaction with a conserved active site tyrosine. This study has identified important limitations associated with mechanism-inspired inhibitor design for GH99 enzymes.
dc.languageEnglish
dc.publisherWILEY-V C H VERLAG GMBH
dc.titleExploration of Strategies for Mechanism-Based Inhibitor Design for Family GH99 endo--1,2-Mannanases
dc.typeJournal Article
dc.identifier.doi10.1002/chem.201800435
melbourne.affiliation.departmentSchool of Chemistry
melbourne.source.titleChemistry: A European Journal
melbourne.source.volume24
melbourne.source.issue29
melbourne.source.pages7464-7473
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1312622
melbourne.contributor.authorWilliams, Spencer
dc.identifier.eissn1521-3765
melbourne.accessrightsOpen Access


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