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Find video protocols related to scientific articles indexed in Pubmed.
Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents.
J. Med. Chem.
PUBLISHED: 08-27-2013
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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 ?M against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria.
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Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity.
J. Med. Chem.
PUBLISHED: 03-19-2013
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Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 ?M for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.