title: Evaluation of monovalent and multivalent iminosugars to modulate Candida albicans β-1,2-mannosyltransferase activities.
abstract: 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.
authors: UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, CNRS, F 59000 Lille, France; CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, Inserm, F-59000 Lille, France.
authors: Thomas
authors: T
authors: Hurtaux
authors: UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, CNRS, F 59000 Lille, France.
authors: Ghenima
authors: G
authors: Sfihi-Loualia
authors: CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, LUNAM Université, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
authors: Yoan
authors: Y
authors: Brissonnet
authors: UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, CNRS, F 59000 Lille, France.
authors: Julie
authors: J
authors: Bouckaert
authors: Département de Chimie, Sorbonne Universités-UPMC Univ Paris 06, École Normale Supérieure-PSL Research University, CNRS UMR 7203 LBM, 24, rue Lhomond, 75005 Paris, France.
authors: Jean-Maurice
authors: JM
authors: Mallet
authors: CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, Inserm, F-59000 Lille, France.
authors: Boualem
authors: B
authors: Sendid
authors: UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, CNRS, F 59000 Lille, France.
authors: Florence
authors: F
authors: Delplace
authors: UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, CNRS, F 59000 Lille, France.
authors: Emeline
authors: E
authors: Fabre
authors: CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, LUNAM Université, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
authors: Sébastien G
authors: SG
authors: Gouin
authors: UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, CNRS, F 59000 Lille, France. Electronic address: Yann.guerardel@univ-lille1.fr.
authors: Yann
authors: Y
authors: Guérardel
mesh_terms: D017485:1-Deoxynojirimycin / Q000138:chemical synthesis / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D002473:Cell Wall / Q000187:drug effects / Q000201:enzymology; D003001:Cloning, Molecular; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D050111:Imino Sugars / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D008362:Mannosides / Q000378:metabolism; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D050111:Imino Sugars; D008362:Mannosides; D011994:Recombinant Proteins; C501633:deoxynojirimycine; D017485:1-Deoxynojirimycin; D008364:Mannosyltransferases; C106904:beta-1,2-mannosyltransferase IV; D005944:Glucosamine
keywords: Iminosugars; Inhibition; Mannosyltransferase; Multivalency; Yeast