Defined stereoisomers of 2â³-amino NAD+ and their activity against human sirtuins and a bacterial (ADP-ribosyl) transferase.
Bioorg Med Chem
; 68: 116875, 2022 08 15.
Article
em En
| MEDLINE
| ID: mdl-35716588
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 2â³-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 2â³-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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sirtuínas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Alemanha