Chemical probes of UDP-galactopyranose mutase.
Many pathogenic prokaryotes and eukaryotes possess the machinery required to assemble galactofuranose (Galf)-containing glycoconjugates; these glycoconjugates can be critical for virulence or viability. Accordingly, compounds that block Galf incorporation may serve as therapeutic leads or as probes of the function of Galf-containing glycoconjugates. The enzyme UDP-galactopyranose mutase (UGM) is the only known generator of UDP-galactofuranose, the precursor to Galf residues. We previously employed a high-throughput fluorescence polarization assay to investigate the Klebsiella pneumoniae UGM. We demonstrate the generality of this assay by extending it to UGM from Mycobacterium tuberculosis. To identify factors influencing binding, we synthesized a directed library containing a 5-arylidene-2-thioxo-4-thiazolidinone core, a structure possessing features common to ligands for both homologs. Our studies offer a blueprint for identifying inhibitors of the growing family of UGM homologs and provide insight into UGM inhibition.
Carlson
Erin E
EE
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
May
John F
JF
Kiessling
Laura L
LL
D001665:Binding Sites; D005690:Galactose / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007711:Klebsiella pneumoniae / Q000201:enzymology; D008024:Ligands; D008958:Models, Molecular; D015336:Molecular Probe Techniques; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014530:Uridine Diphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D015335:Molecular Probes; D013844:Thiazoles; C104136:uridine diphosphate galactofuranose; D014530:Uridine Diphosphate; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase; D005690:Galactose