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Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15957-15966. doi: 10.1073/pnas.1902346116. Epub 2019 Jul 24.

Identification of evolutionary and kinetic drivers of NAD-dependent signaling.

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Department of Arctic and Marine Biology, UiT The Arctic University of Norway, 9017 Tromsø, Norway.
Department of Biological Sciences, University of Bergen, 5006 Bergen, Norway.
Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
Department of Animal and Plant Sciences, Western Bank, University of Sheffield, S10 2TN Sheffield, United Kingdom.
Department of Animal Behaviour, Bielefeld University, 33501 Bielefeld, Germany.
Department of Physics, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
Steinbuch Centre for Computing, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
John von Neumann Institute for Computing, Jülich Supercomputing Centre, Forschungszentrum Jülich, 52425 Jülich, Germany.
Department of Arctic and Marine Biology, UiT The Arctic University of Norway, 9017 Tromsø, Norway;


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.


NAD pathway dynamics and evolution; NAD-dependent signaling and biosynthesis; mathematical modeling; nicotinamide N-methyltransferase (NNMT); nicotinamide phosphoribosyltransferase (NamPT)

[Available on 2020-01-24]

Conflict of interest statement

The authors declare no conflict of interest.

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