Iminodiacetic-phosphoramidates as metabolic prototypes for diversifying nucleic acid polymerization in vivo.

Nucleic Acids Research
Anne GirautPiet Herdewijn

Abstract

Previous studies in our laboratory proved that certain functional groups are able to mimic the pyrophosphate moiety and act as leaving groups in the enzymatic polymerization of deoxyribonucleic acids by HIV-1 reverse transcriptase. When the potential leaving group possesses two carboxylic acid moieties linked to the nucleoside via a phosphoramidate bond, it is efficiently recognized by this error-prone enzyme, resulting in nucleotide incorporation into DNA. Here, we present a new efficient alternative leaving group, iminodiacetic acid, which displays enhanced kinetics and an enhanced elongation capacity compared to previous results obtained with amino acid deoxyadenosine phosphoramidates. Iminodiacetic acid phosphoramidate of deoxyadenosine monophosphate (IDA-dAMP) is processed by HIV-1 RT as a substrate for single nucleotide incorporation and displays a typical Michaelis-Menten kinetic profile. This novel substrate also proved to be successful in primer strand elongation of a seven-base template overhang. Modelling of this new substrate in the active site of the enzyme revealed that the interactions formed between the triphosphate moiety, magnesium ions and enzyme's residues could be different from those of the natural triphos...Continue Reading

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Citations

Mar 19, 2011·Journal of Medicinal Chemistry·Nicholas A Meanwell
Sep 6, 2011·Nucleosides, Nucleotides & Nucleic Acids·Shiqiong Yang, Piet Herdewijn
Nov 15, 2011·The Journal of Physical Chemistry. a·Servaas MichielssensArnout Ceulemans
Jun 20, 2012·FEBS Letters·P Herdewijn, P Marlière
Aug 22, 2014·Chemical Reviews·Ugo PradereRaymond F Schinazi
Apr 23, 2013·ChemMedChem·Munmun MaitiPiet Herdewijn
Oct 2, 2012·Chembiochem : a European Journal of Chemical Biology·Anne GirautPiet Herdewijn
Jun 30, 2011·Chembiochem : a European Journal of Chemical Biology·Xiao-Ping SongPiet Herdewijn
Dec 21, 2012·Chemistry & Biodiversity·Xiao-Ping SongPiet Herdewijn
Apr 8, 2015·Organic & Biomolecular Chemistry·Munmun MaitiPiet Herdewijn
Nov 26, 2010·Organic & Biomolecular Chemistry·Shiqiong YangPiet Herdewijn
Jan 27, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Algirdas MikalkėnasSaulius Serva
Oct 8, 2020·World Journal of Virology·Yao-Ying XieXiao-Yu Liao

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Methods Mentioned

BETA
enzymatic assay
column chromatography
electrophoresis
chemical modification

Software Mentioned

Bobscript
Optiquant
Molscript
Raster3d
GraphPad Prism
Bruker Topspin TM

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