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Synthesis of Stable NAD+ Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC.
Madern, Jerre M; Kim, Robbert Q; Misra, Mohit; Dikic, Ivan; Zhang, Yong; Ovaa, Huib; Codée, Jeroen D C; Filippov, Dmitri V; van der Heden van Noort, Gerbrand J.
Affiliation
  • Madern JM; Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
  • Kim RQ; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
  • Misra M; Institute of Biochemistry II, Goethe University Faculty of Medicine, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
  • Dikic I; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438, Frankfurt am, Main, Germany.
  • Zhang Y; Institute of Biochemistry II, Goethe University Faculty of Medicine, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
  • Ovaa H; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438, Frankfurt am, Main, Germany.
  • Codée JDC; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
  • Filippov DV; Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Centre, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
  • van der Heden van Noort GJ; Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
Chembiochem ; 21(20): 2903-2907, 2020 10 15.
Article in En | MEDLINE | ID: mdl-32421893
ABSTRACT
Stable NAD+ analogues carrying single atom substitutions in either the furanose ring or the nicotinamide part have proven their value as inhibitors for NAD+ -consuming enzymes. To investigate the potential of such compounds to inhibit the adenosine diphosphate ribosyl (ADPr) transferase activity of the Legionella SdeC enzyme, we prepared three NAD+ analogues, namely carbanicotinamide adenosine dinucleotide (c-NAD+ ), thionicotinamide adenosine dinucleotide (S-NAD+ ) and benzamide adenosine dinucleotide (BAD). We optimized the chemical synthesis of thionicotinamide riboside and for the first time used an enzymatic approach to convert all three ribosides into the corresponding NAD+ mimics. We thus expanded the known scope of substrates for the NRK1/NMNAT1 enzyme combination by turning all three modified ribosides into NAD+ analogues in a scalable manner. We then compared the three NAD+ mimics side-by-side in a single assay for enzyme inhibition on Legionella effector enzyme SdeC. The class of SidE enzymes to which SdeC belongs was recently identified to be important in bacterial virulence, and we found SdeC to be inhibited by S-NAD+ and BAD with IC50 values of 28 and 39 µM, respectively.
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Full text: 1 Database: MEDLINE Main subject: Legionella pneumophila / Poly(ADP-ribose) Polymerases / Poly(ADP-ribose) Polymerase Inhibitors / NAD Language: En Journal: Chembiochem Journal subject: BIOQUIMICA Year: 2020 Type: Article Affiliation country: Netherlands

Full text: 1 Database: MEDLINE Main subject: Legionella pneumophila / Poly(ADP-ribose) Polymerases / Poly(ADP-ribose) Polymerase Inhibitors / NAD Language: En Journal: Chembiochem Journal subject: BIOQUIMICA Year: 2020 Type: Article Affiliation country: Netherlands