1. Identification of evolutionary and kinetic drivers of NAD-dependent signaling
- Author
-
Dorothée Houry, Ines Heiland, Alexander Schug, Toni I. Gossmann, Ines Reinartz, Mathias Bockwoldt, Marc Niere, and Mathias Ziegler
- Subjects
Bioenergetics ,Nicotinamide phosphoribosyltransferase ,Nicotinamide adenine dinucleotide ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ribose ,Nicotinamide N-Methyltransferase ,Animals ,Humans ,Amino Acid Sequence ,Nicotinamide Phosphoribosyltransferase ,Phylogeny ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,VDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470::Molekylærbiologi: 473 ,Nicotinamide ,VDP::Mathematics and natural science: 400::Basic biosciences: 470::Molecular biology: 473 ,Metabolism ,NAD ,Biological Evolution ,Cell biology ,Biosynthetic Pathways ,Kinetics ,chemistry ,PNAS Plus ,030220 oncology & carcinogenesis ,Vertebrates ,NAD+ kinase ,ddc:500 ,Signal transduction ,HeLa Cells ,Signal Transduction - Abstract
Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. NAD-dependent signaling (e.g., by sirtuins and poly–adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.
- Published
- 2019