Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents

Keough, Dianne T., Hocková, Dana, Rejman, Dominik, Spaček, Petr, Vrbková, Silvie, Krečmerová, Marcela, Eng, Wai Soon, Jans, Harmen, West, Nicholas P., Naesens, Lieve M. J., de Jersey, John and Guddat, Luke W. (2013) Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents. Journal of Medicinal Chemistry, 56 17: 6967-6984. doi:10.1021/jm400779n


Author Keough, Dianne T.
Hocková, Dana
Rejman, Dominik
Spaček, Petr
Vrbková, Silvie
Krečmerová, Marcela
Eng, Wai Soon
Jans, Harmen
West, Nicholas P.
Naesens, Lieve M. J.
de Jersey, John
Guddat, Luke W.
Title Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents
Formatted title
Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2013-09
Sub-type Article (original research)
DOI 10.1021/jm400779n
Volume 56
Issue 17
Start page 6967
End page 6984
Total pages 18
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2014
Language eng
Formatted abstract
Escherichia coli (Ec) cells possess two purine salvage enzymes: xanthine-guanine phosphoribosyltransferase (XGPRT) and hypoxanthine phosphoribosyltransferase (HPRT). EcXGPRT shares a common structural feature with other members of this family, a flexible loop that closes over the active site during catalysis. The replacement of six of these amino acids by alanine has no effect on the Km for the two substrates. However, the Ki for the nucleoside monophosphate increases by 27-fold, and the kcat is reduced by 200-fold. Nucleoside phosphonates (NP) are good inhibitors of EcXGPRT and EcHPRT, with Ki values as low as 10 nM. In the absence of the flexible loop, these values increase by 5- to 30-fold, indicating the importance of the loop for high-affinity inhibition. Crystal structures of two NPs in complex with EcXGPRT explain the tight binding. Prodrugs of NPs with low Ki values for EcXGPRT or EcHPRT exhibit IC50 values between 5 and 23 μM against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 15 Nov 2013, 13:57:55 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences