N (6)-substituted AMPs inhibit mammalian deoxynucleotide N-hydrolase DNPH1

Claire Amiable; Sylvie Pochet; André Padilla; Gilles Labesse; Pierre Alexandre Kaminski

doi:10.1371/journal.pone.0080755

N (6)-substituted AMPs inhibit mammalian deoxynucleotide N-hydrolase DNPH1

PLoS One. 2013 Nov 19;8(11):e80755. doi: 10.1371/journal.pone.0080755. eCollection 2013.

Authors

Claire Amiable¹, Sylvie Pochet, André Padilla, Gilles Labesse, Pierre Alexandre Kaminski

Affiliation

¹ Institut Pasteur, Unité de Chimie et Biocatalyse, Paris, France ; CNRS, UMR3523, Paris, France ; Université Paris Descartes Sorbonne Paris Cité, Paris, France.

Abstract

The gene dnph1 (or rcl) encodes a hydrolase that cleaves the 2'-deoxyribonucleoside 5'-monophosphate (dNMP) N-glycosidic bond to yield a free nucleobase and 2-deoxyribose 5-phosphate. Recently, the crystal structure of rat DNPH1, a potential target for anti-cancer therapies, suggested that various analogs of AMP may inhibit this enzyme. From this result, we asked whether N (6)-substituted AMPs, and among them, cytotoxic cytokinin riboside 5'-monophosphates, may inhibit DNPH1. Here, we characterized the structural and thermodynamic aspects of the interactions of these various analogs with DNPH1. Our results indicate that DNPH1 is inhibited by cytotoxic cytokinins at concentrations that inhibit cell growth.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Monophosphate / analogs & derivatives
Adenosine Monophosphate / chemistry
Adenosine Monophosphate / metabolism
Adenosine Monophosphate / pharmacology*
Amino Acid Sequence
Animals
Catalytic Domain
Enzyme Activation / drug effects
Humans
Kinetics
Models, Molecular
Molecular Conformation
Molecular Sequence Data
N-Glycosyl Hydrolases / chemistry
N-Glycosyl Hydrolases / genetics
N-Glycosyl Hydrolases / metabolism*
Nuclear Proteins / chemistry
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Protein Binding
Proto-Oncogene Proteins / chemistry
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Rats
Sequence Alignment
Thermodynamics

Substances

Nuclear Proteins
Proto-Oncogene Proteins
Adenosine Monophosphate
DNPH1 protein, human
DNPH1 protein, rat
N-Glycosyl Hydrolases

Grants and funding

This work was financially supported by the Institut Pasteur, CNRS, Fondation pour la Recherche Medicale (DCM20111223063 to S. Pochet) and by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01. C. Amiable was recipient of a fellowship from the French Ministry of Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.