title: N (6)-substituted AMPs inhibit mammalian deoxynucleotide N-hydrolase DNPH1.
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.
authors.affiliation: Institut Pasteur, Unité de Chimie et Biocatalyse, Paris, France ; CNRS, UMR3523, Paris, France ; Université Paris Descartes Sorbonne Paris Cité, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Amiable
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pochet
authors.forename: André
authors.initials: A
authors.lastname: Padilla
authors.forename: Gilles
authors.initials: G
authors.lastname: Labesse
authors.forename: Pierre Alexandre
authors.initials: PA
authors.lastname: Kaminski
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment; D013816:Thermodynamics
chemical_list: D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000249:Adenosine Monophosphate; C107935:DNPH1 protein, human; C518894:DNPH1 protein, rat; D009699:N-Glycosyl Hydrolases