title: Synthetic UDP-furanoses as potent inhibitors of mycobacterial galactan biogenesis.
abstract: UDP-galactofuranose (UDP-Galf) is a substrate for two types of enzymes, UDP-galactopyranose mutase and galactofuranosyltransferases, which are present in many pathogenic organisms but absent from mammals. In particular, these enzymes are involved in the biosynthesis of cell wall galactan, a polymer essential for the survival of the causative agent of tuberculosis, Mycobacterium tuberculosis. We describe here the synthesis of derivatives of UDP-Galf modified at C-5 and C-6 using a chemoenzymatic route. In cell-free assays, these compounds prevented the formation of mycobacterial galactan, via the production of short "dead-end" intermediates resulting from their incorporation into the growing oligosaccharide chain. Modified UDP-furanoses thus constitute novel probes for the study of the two classes of enzymes involved in mycobacterial galactan assembly, and studies with these compounds may ultimately facilitate the future development of new therapeutic agents against tuberculosis.
authors.affiliation: Ecole Nationale Supérieure de Chimie de Rennes, CNRS, UMR 6226, 35708 Rennes, Cedex 7, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Peltier
authors.forename: Martina
authors.initials: M
authors.lastname: Beláňová
authors.forename: Petronela
authors.initials: P
authors.lastname: Dianišková
authors.forename: Ruokun
authors.initials: R
authors.lastname: Zhou
authors.forename: Ruixiang Blake
authors.initials: RB
authors.lastname: Zheng
authors.forename: Jean A
authors.initials: JA
authors.lastname: Pearcey
authors.forename: Maju
authors.initials: M
authors.lastname: Joe
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Brennan
authors.forename: Caroline
authors.initials: C
authors.lastname: Nugier-Chauvin
authors.forename: Vincent
authors.initials: V
authors.lastname: Ferrières
authors.forename: Todd L
authors.initials: TL
authors.lastname: Lowary
authors.forename: Richard
authors.initials: R
authors.lastname: Daniellou
authors.forename: Katarína
authors.initials: K
authors.lastname: Mikušová
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005685:Galactans / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005690:Galactose / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000201:enzymology; D020102:Mycobacterium smegmatis / Q000201:enzymology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D005685:Galactans; D011994:Recombinant Proteins; C104136:uridine diphosphate galactofuranose; D014530:Uridine Diphosphate; D005700:Galactosyltransferases; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase; D005690:Galactose