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. 2009 Jan 1;11(1):193-6.
doi: 10.1021/ol802094p.

Potent Ligands for Prokaryotic UDP-galactopyranose Mutase That Exploit an Enzyme Subsite

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Free PMC article

Potent Ligands for Prokaryotic UDP-galactopyranose Mutase That Exploit an Enzyme Subsite

Emily C Dykhuizen et al. Org Lett. .
Free PMC article

Abstract

UDP-galactopyranose mutase (UGM or Glf), which catalyzes the interconversion of UDP-galactopyranose and UDP-galactofuranose, is implicated in the viability and virulence of multiple pathogenic microorganisms. Here we report the synthesis of high-affinity ligands for UGM homologues from Klebsiella pneumoniae and Mycobacterium tuberculosis. The potency of these compounds stems from their ability to access both the substrate binding pocket and an adjacent site.

Figures

Figure 1
Figure 1
The reaction catalyzed by UGM
Figure 2
Figure 2
Relative affinity of conjugates 3a–3e for UGM. The affinities are shown relative to that of UDP (1). An increase is observed as the alkyl linker separating the UDP and fluorescein moieties is extended.
Figure 3
Figure 3
Oligoethylene glycol containing conjugates bind to UGM with decreased affinity compared to alkyl containing conjugates.
Figure 4
Figure 4
No UGM binding is detectable for the simple fluorescein derivative 5.
Figure 5
Figure 5
Aryl substituents, such as naphthyl, are able to occupy the subsite occupied by the fluorescein group.
Scheme 1
Scheme 1
Synthesis of UDP-fluorescein conjugates.
Scheme 2
Scheme 2
Synthesis of a non-substrate-based UGM inhibitor that incorporates fluorescein

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