title: Sugar nucleotide recognition by Klebsiella pneumoniae UDP-D-galactopyranose mutase: fluorinated substrates, kinetics and equilibria.
abstract: A series of selectively fluorinated and other substituted UDP-D-galactose derivatives have been evaluated as substrates for Klebsiella pneumoniae UDP-D-galactopyranose mutase. This enzyme, which catalyses the interconversion of the pyranose and furanose forms of galactose as its UDP adduct, is a prospective drug target for a variety of microbial infections. We show that none of the 2''-, 3''- or 6''-hydroxyl groups of UDP-D-galactopyranose are essential for substrate binding and turnover. However, steric factors appear to play an important role in limiting the range of substitutions that can be accommodated at C-2'' and C-6'' of the sugar nucleotide substrate. Attempts to invert the C-2'' stereochemistry from equatorial to axial, changing D-galacto- to D-talo-configuration, in an attempt to exploit the higher percentage of furanose at equilibrium in the talo-series, met with no turnover of substrate.
authors.affiliation: School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR47TJ, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Errey
authors.forename: Maretta C
authors.initials: MC
authors.lastname: Mann
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Fairhurst
authors.forename: Lionel
authors.initials: L
authors.lastname: Hill
authors.forename: Michael R
authors.initials: MR
authors.lastname: McNeil
authors.forename: James H
authors.initials: JH
authors.lastname: Naismith
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Percy
authors.forename: Chris
authors.initials: C
authors.lastname: Whitfield
authors.forename: Robert A
authors.initials: RA
authors.lastname: Field
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry; D016503:Drug Delivery Systems; D005461:Fluorine; D019751:Intramolecular Transferases / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D007711:Klebsiella pneumoniae / Q000201:enzymology*; D009711:Nucleotides; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D009711:Nucleotides; D005461:Fluorine; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase