Errey James C, Mann Maretta C, Fairhurst Shirley A, Hill Lionel, McNeil Michael R, Naismith James H, Percy Jonathan M, Whitfield Chris, Field Robert A
School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR47TJ, UK.
Org Biomol Chem. 2009 Mar 7;7(5):1009-16. doi: 10.1039/b815549f. Epub 2009 Jan 23.
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.
一系列选择性氟化及其他取代的UDP-D-半乳糖衍生物已被评估作为肺炎克雷伯菌UDP-D-吡喃半乳糖变位酶的底物。该酶催化半乳糖作为其UDP加合物的吡喃糖和呋喃糖形式的相互转化，是多种微生物感染的潜在药物靶点。我们发现，UDP-D-吡喃半乳糖的2''-、3''-或6''-羟基对于底物结合和周转并非必不可少。然而，空间因素似乎在限制糖核苷酸底物C-2''和C-6''处可容纳的取代范围方面起着重要作用。试图将C-2''的立体化学从平伏键反转到直立键，将D-半乳糖构型变为D-塔罗构型，以利用塔罗系列中平衡时呋喃糖的更高比例，但未观察到底物周转。
