Sugar nucleotide recognition by Klebsiella pneumoniae UDP-D-galactopyranose mutase: fluorinated substrates, kinetics and equilibria.
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.
Errey
James C
JC
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR47TJ, UK.
Mann
Maretta C
MC
Fairhurst
Shirley A
SA
Hill
Lionel
L
McNeil
Michael R
MR
Naismith
James H
JH
Percy
Jonathan M
JM
Whitfield
Chris
C
Field
Robert A
RA
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
D000900:Anti-Bacterial Agents; D009711:Nucleotides; D005461:Fluorine; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase