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PMID:22428584
| Citation |
Yoshida, T, Nasu, H, Namba, E, Ubukata, O and Yamashita, M (2012) Discovery of a compound which acts as a bacterial UMP kinase PyrH inhibitor. FEMS Microbiol. Lett. 330:121-6 |
|---|---|
| Abstract |
PyrH is a member of the UMP kinase family that catalyses the conversion of UMP to UDP, an essential step in the pyrimidine metabolic pathway in a variety of bacteria including those causing community-acquired respiratory tract infections (RTIs). In this study, we have developed a luminescence-based kinase assay of PyrH and evaluated the inhibitory activity of PYRH-1 (sodium {3-[4-tert-butyl-3-(9H-xanthen-9-ylacetylamino)phenyl]-1-cyclohexylmethylpropoxycarbonyloxy}acetate). PYRH-1 inhibits PyrH derived from both Streptococcus pneumoniae and Haemophilus influenzae with IC(50) (concentration of inhibitor giving a 50% decrease in enzyme activity) values of 48 and 75 μM, respectively, whose inhibitory activity against S. pneumoniae PyrH was far higher compared with that of UTP (IC(50) = 710 μM), an allosteric PyrH inhibitor. The molecular interaction analysis by surface plasmon resonance suggested that PYRH-1 directly interacts with S. pneumoniae PyrH at one-to-one molar ratio. Finally, PYRH-1 was shown to have antimicrobial activity against several different bacteria causing RTIs, such as S. pneumoniae, Staphylococcus aureus, H. influenzae (acrA knockout strain), suggesting that PYRH-1 is a prototype chemical compound that can be harnessed as an antimicrobial drug with a novel mode of action by targeting bacterial PyrH. |
| Links |
PubMed Online version:10.1111/j.1574-6968.2012.02546.x |
| Keywords |
Enzyme Inhibitors/isolation & purification; Enzyme Inhibitors/metabolism; Haemophilus influenzae/drug effects; Haemophilus influenzae/enzymology; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Nucleoside-Phosphate Kinase/antagonists & inhibitors; Nucleoside-Phosphate Kinase/metabolism; Protein Binding; Staphylococcus aureus/drug effects; Streptococcus pneumoniae/drug effects; Streptococcus pneumoniae/enzymology; Surface Plasmon Resonance; Uridine Diphosphate/metabolism; Uridine Monophosphate/metabolism |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0033862: UMP kinase activity |
ECO:0000314: |
F |
Figure 2: UMP kinase activity assays was used to evaluate PyrH kinase activity of S. pneumoniae and H. influenzae verse a sterilized water control. The amount of residual substrate left over, either ATP (labeled RLU) or UMP, was scaled in relative luminescence units versus time. The luminescence units left over were correlated to the amount of PyrH added. |
complete | ||||
| GO:0033862: UMP kinase activity |
ECO:0000314: |
F |
Figure 2: UMP kinase activity assays was used to evaluate PyrH kinase activity of S. pneumoniae and H. influenzae verse a sterilized water control. The amount of residual substrate left over, either ATP (labeled RLU) or UMP, was scaled in relative luminescence units versus time. The luminescence units left over were correlated to the amount of PyrH added. |
complete | ||||
See also
References
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