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

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
Description	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 muM against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria. 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 muM against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria. (en)
Title	Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents (en)
skos:prefLabel	Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents (en)
skos:notation	RIV/61388963:_____/13:00421911!RIV14-GA0-61388963
http://linked.open...avai/riv/aktivita	I P
http://linked.open...avai/riv/aktivity	I, P(GAP207/11/0108)
http://linked.open...iv/cisloPeriodika	17
http://linked.open...vai/riv/dodaniDat	2014
http://linked.open...aciTvurceVysledku	Vrbková, Silvie Špaček, Petr Krečmerová, Marcela Hocková, Dana Rejman, Dominik
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Ústav organické chemie a biochemie AV ČR, v. v. i.
http://linked.open...dnocenehoVysledku	80213
http://linked.open...ai/riv/idVysledku	RIV/61388963:_____/13:00421911
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	nucleoside phosphonates; antibacterial agents; hypoxanthine-guanine phosphoribosyltransferase; state analog inhibitor; antimalarial chemotherapy (en)
http://linked.open.../riv/klicoveSlovo	nucleoside phosphonates antimalarial chemotherapy hypoxanthine-guanine phosphoribosyltransferase state analog inhibitor antibacterial agents
http://linked.open...odStatuVydavatele	US - Spojené státy americké
http://linked.open...ontrolniKodProRIV	[D5C726E1F802]
http://linked.open...i/riv/nazevZdroje	Journal of Medicinal Chemistry
http://linked.open...in/vavai/riv/obor	CC
http://linked.open...ichTvurcuVysledku	5 (xsd:int)
http://linked.open...cetTvurcuVysledku	12 (xsd:int)
http://linked.open...vavai/riv/projekt	Novel types of acyclic nucleoside phosphonates with potential antimalarial activity:hypoxanthine-guanine-xanthine phosphoribosyltransferase inhibitors
http://linked.open...UplatneniVysledku	2013
http://linked.open...v/svazekPeriodika	56
http://linked.open...iv/tvurceVysledku	Hocková, Dana Krečmerová, Marcela Špaček, Petr Rejman, Dominik Guddat, L. W. Keough, D. T. de Jersey, J. Eng, W. S. Jans, H. Naesens, L. M. J. Vrbková, Silvie West, N. P.
http://linked.open...ain/vavai/riv/wos	000330097400034
issn	0022-2623
number of pages	18 (xsd:int)
http://bibframe.org/vocab/doi	10.1021/jm400779n

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