Defined stereoisomers of 2″-amino NAD+ and their activity against human sirtuins and a bacterial (ADP-ribosyl) transferase

Sarah Zähringer, Tobias Rumpf, Jelena Melesina, Alexander E. Lang, Klaus Aktories, Wolfgang Sippl, Manfred Jung, Gerd K. Wagner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
45 Downloads (Pure)

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an important biomolecule with essential roles at the intersection of energy metabolism, epigenetic regulation and cell signalling. Synthetic analogues of NAD+ are therefore of great interest as chemical tools for medicinal chemistry, chemical biology and drug discovery. Herein, we report the chemical synthesis and full analytical characterisation of three stereoisomers of 2″-amino NAD+, and their biochemical evaluation against two classes of NAD+-consuming enzymes: the human sirtuins 1–3, and the bacterial toxin TccC3. To rationalise the observed activities, molecular docking experiments were carried out with SIRT1 and SIRT2, which identified the correct orientation of the pyrophosphate linkage as a major determinant for activity in this series. These results, together with results from stability tests and a conformational analysis, allow, for the first time, a side-by-side comparison of the chemical and biochemical features, and analytical properties, of different 2″-amino NAD+ stereoisomers. Our findings provide insight into the recognition of co-substrate analogues by sirtuins, and will greatly facilitate the application of these important NAD+ analogues as chemical tool compounds for mechanistic studies with these as well as other NAD+-dependent enyzmes.

Original languageEnglish
Article number116875
Number of pages11
JournalBioorganic & Medicinal Chemistry
Volume68
Early online date15 Jun 2022
DOIs
Publication statusPublished - 15 Aug 2022

Keywords

  • NAD - metabolism
  • Sirtuins - metabolism
  • Sirtuin 2 - metabolism
  • Chemical tool
  • Nicotinamide adenine dinucleotide
  • Stereochemistry
  • Molecular Docking Simulation
  • Adenosine Diphosphate
  • Stereoisomerism
  • Sirtuin
  • Humans
  • Epigenesis, Genetic
  • ADP-ribosyltransferase
  • Transferases - metabolism

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