Document Detail

2-Fluoro-ATP as a versatile tool for 19F NMR-based activity screening.
MedLine Citation:
PMID:  18407634     Owner:  NLM     Status:  MEDLINE    
19F NMR-based methods have found utility in activity-based screening assays. However, because enzymes catalyze a diverse set of reactions, a large variety of fluorinated substrates would need to be identified to target each one separately. We have developed a more streamlined approach that is applicable to many enzymes that utilize ATP as a substrate. In this method, a fluorine-containing ATP analogue, 2-fluoro-ATP, is used to monitor the reaction. Applications are described for nicotinamide adenine dinucleotide synthetase and 3-phosphoinositide dependent kinase-1. Fragment screening results for the latter indicate that this technique can identify compounds that inhibit as well as activate reactions. The present results, together with previous biochemical studies from other laboratories, have shown that 2-fluoro-ATP can serve as a substrate for nine enzymes that are representative of three of the six enzyme subclasses, namely the transferases, hydrolases, and ligases. This suggests that 2-fluoro-ATP is suitable as a universal tool for screening ATP-requiring enzymes. Importantly, 2-fluoro-ATP has been determined to be a valid substrate for a variety of kinases, including both small molecule and protein kinases, suggesting that it may be useful for investigating the large number of pharmaceutically relevant kinases.
Brian J Stockman
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Publication Detail:
Type:  Journal Article     Date:  2008-04-12
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  130     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-04-30     Completed Date:  2008-06-23     Revised Date:  2008-12-15    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5870-1     Citation Subset:  IM    
Pfizer Global Research & Development, Groton, Connecticut 06340, USA.
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MeSH Terms
Adenosine Triphosphate / analogs & derivatives*,  chemistry,  metabolism
Enzymes / analysis*,  metabolism
Fluorine / chemistry
Nuclear Magnetic Resonance, Biomolecular / methods*
Nucleoside-Phosphate Kinase / analysis,  metabolism
Protein-Serine-Threonine Kinases / analysis,  metabolism
Substrate Specificity
Reg. No./Substance:
0/Enzymes; 1492-62-2/2-fluoro-ATP; 56-65-5/Adenosine Triphosphate; 7782-41-4/Fluorine; EC Kinases; EC dehydrogenase (acetyl-transferring) kinase; EC Kinase; EC kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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