Kinetic analysis of N-alkylaryl carboxamide hexitol nucleotides as substrates for evolved polymerases

DNA directed DNA polymerase; Article; DNA modification; DNA-Directed DNA Polymerase; Kinetics; Nucleotides; Protein Engineering; Substrate Specificity; Sugar Alcohols

Abstract :

[en] Six 1,5-anhydrohexitol uridine triphosphates were synthesized with aromatic substitutions appended via a carboxamide linker to the 5-position of their bases. An improved method for obtaining such 5-substituted hexitol nucleosides and nucleotides is described. The incorporation profile of the nucleotide analogues into a DNA duplex overhang using recently evolved XNA polymerases is compared. Long, mixed HNA sequences featuring the base modifications are generated. The apparent binding affinity of four of the nucleotides to the enzyme, the rate of the chemical step and of product release, plus the specificity constant for the incorporation of these modified nucleotides into a DNA duplex overhang using the HNA polymerase T6G12 I521L are determined via pre-steady-state kinetics. HNA polymers displaying aromatic functional groups could have significant impact on the isolation of stable and high-affinity binders and catalysts, or on the design of nanomaterials. © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License

Disciplines :

Microbiology

Author, co-author :

Renders, M.; KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Rega, Herestraat 49 box 1041, Leuven, 3000, Belgium

Dumbre, S.; KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Rega, Herestraat 49 box 1041, Leuven, 3000, Belgium

Abramov, M.; KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Rega, Herestraat 49 box 1041, Leuven, 3000, Belgium

Kestemont, D.; KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Rega, Herestraat 49 box 1041, Leuven, 3000, Belgium

Margamuljana, L.; KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Rega, Herestraat 49 box 1041, Leuven, 3000, Belgium

Largy, E.; ARNA laboratory, Université de Bordeaux, INSERM U1212, CNRS UMR5320, IECB, 2 rue Robert Escarpit, Pessac, 33600, France

Cozens, C.; Structural and Molecular Biology Department, University College London, Gower Street, London, WC1E B6T, United Kingdom, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, United Kingdom, LabGenius Ltd, B201.3 Biscuit Factory, 100 Drummond Road, London, SE16 4DG, United Kingdom

Vandenameele, Julie ; Université de Liège - ULiège > Département des sciences de la vie > Enzymologie et repliement des protéines

Pinheiro, V. B.; Structural and Molecular Biology Department, University College London, Gower Street, London, WC1E B6T, United Kingdom, Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, United Kingdom, KU Leuven, Rega Inst. for Medical Research, Medicinal Chemistry, Rega, Herestraat 49 box 1041, Leuven, 3000, Belgium

Toye, Dominique ; Université de Liège - ULiège > Department of Chemical Engineering > Génie de la réaction et des réacteurs chimiques

Frère, Jean-Marie ; Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques

Herdewijn, P.; KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Rega, Herestraat 49 box 1041, Leuven, 3000, Belgium, Université d’Evry, CNRS-UMR8030/Laboratoire iSSB, CEA, DRF, IG, Genoscope, Université Paris-Saclay, Evry, 91000, France

Language :

English

Title :

Kinetic analysis of N-alkylaryl carboxamide hexitol nucleotides as substrates for evolved polymerases

Publication date :

2019

Journal title :

Nucleic Acids Research

ISSN :

0305-1048

eISSN :

1362-4962

Publisher :

Oxford University Press

Volume :

Issue :

Pages :

2160-2168

Peer reviewed :

Peer Reviewed verified by ORBi

Name of the research project :

ERC-2012-ADG 20120216/ 3206831247114N, 16100518, DGO6, 1318159

Funders :

CER - Conseil Européen de la Recherche [BE]

Available on ORBi :

since 02 July 2020

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