Evaluation of monovalent and multivalent iminosugars to modulate Candida albicans β-1,2-mannosyltransferase activities

• Published in: Carbohydrate research Vol. 429; pp. 123 - 127
• Main Authors: Hurtaux, Thomas, Sfihi-Loualia, Ghenima, Brissonnet, Yoan, Bouckaert, Julie, Mallet, Jean-Maurice, Sendid, Boualem, Delplace, Florence, Fabre, Emeline, Gouin, Sébastien G., Guérardel, Yann
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 24-06-2016; Elsevier
• Subjects: 1-Deoxynojirimycin - chemical synthesis; 1-Deoxynojirimycin - pharmacology; Candida albicans - drug effects; Candida albicans - enzymology; Candida albicans - genetics; Cell Wall - drug effects; Cell Wall - enzymology; Chemical Sciences; Cloning, Molecular; Enzyme Assays; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - genetics; Fungal Proteins - metabolism; Gene Expression; Glucosamine - analogs & derivatives; Glucosamine - chemical synthesis; Glucosamine - pharmacology; Imino Sugars - chemical synthesis; Imino Sugars - pharmacology; Iminosugars; Inhibition; Kinetics; Mannosides - metabolism; Mannosyltransferase; Mannosyltransferases - antagonists & inhibitors; Mannosyltransferases - genetics; Mannosyltransferases - metabolism; Multivalency; Organic chemistry; Pichia - genetics; Pichia - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Substrate Specificity; Yeast; Iminosugars; Yeast; Multivalency; Inhibition; Mannosyltransferase
• ISSN: 0008-6215; 1873-426X; 0008-6215
• DOI: 10.1016/j.carres.2016.01.004

•A library of iminosugars was screened for their effects on mannosyltransferases.•A monovalent deoxynojirimycin derivative inhibits the transfer of mannose.•Deoxymannojirimycin derivatives modulate the substrate specificity of CaBmt1.•Iminosugars may be used for controlling biosynthesis of β-mannosides.
β-1,2-Linked oligomannosides substitute the cell wall of numerous yeast species. Several of those including Candida albicans may cause severe infections associated with high rates of morbidity and mortality, especially in immunocompromised patients. β-1,2-Mannosides are known to be involved in the pathogenic process and to elicit an immune response from the host. In C. albicans, the synthesis of β-mannosides is under the control of a family of nine genes coding for putative β-mannosyltransferases. Two of them, CaBmt1 and CaBmt3, have been shown to initiate and prime the elongation of the β-mannosides on the cell-wall mannan core. In the present study, we have assessed the modulating activities of monovalent and multivalent iminosugar analogs on these enzymes in order to control the enzymatic bio-synthesis of β-mannosides. We have identified a monovalent deoxynojirimycin (DNJ) derivative that inhibits the CaBmt1-catalyzed initiating activity, and mono-, tetra- and polyvalent deoxymannojirimycin (DMJ) that modulate the CaBmt1 activity toward the formation of a single major product. Analysis of the aggregating properties of the multivalent iminosugars showed their ability to elicit clusterization of both CaBmt1 and CaBmt3, without affecting their activity. These results suggest promising roles for multivalent iminosugars as controlling agents for the biosynthesis of β-1,2 mannosides and for monovalent DNJ derivative as a first target for the design of future β-mannosyltransferase inhibitors.