Identification of evolutionary and kinetic drivers of NAD-dependent signaling

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.

(ADP-ribosyl)hydrolases: structure, function, and biology

“…Diversification of NAD + signaling is particularly apparent in vertebrata, being linked to evolutionary optimization of NAD + biosynthesis and increased (ADP-ribosyl) signaling (Bockwoldt et al 2019). ADP-ribosylation is used by organisms from all kingdoms of life and some viruses (Perina et al 2014;Aravind et al 2015) and controls a wide range of cellular processes such as DNA repair, transcription, cell division, protein degradation, and stress response to name a few (Bock and Chang 2016;Gupte et al 2017;Palazzo et al 2017;Rechkunova et al 2019).…”

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

“…In this pathway, Nam N-methyltransefase (NNMT) recently emerged as an evolutionarily conserved regulator of Nam availability. In fact, NNMT N-methylates Nam preventing its accumulation and inhibition of NAD-consuming enzymes, while on the other side, limiting its availability to NAMPT (80,81). The functional NAMPT forms a homodimer to catalyze the conversion of Nam and PRPP to NMN.…”

Reciprocal regulation between nicotinamide adenine dinucleotide metabolism and abscisic acid and stress response pathways in Arabidopsis

“…The de novo biosynthetic pathway consists of three enzymes, AO, QS, and QPT, that catalyze the early steps of NAD biosynthesis in the plastid, which is the primary route for the production of NAD in plant cells [33]. NAD is a key link between energy metabolism and redox reactions and has emerged as a central hub between bioenergetics and all major cellular processes in plants and other organisms [3]. Redox reactions involving electron or energy transfer to oxygen produce ROS under normal and particularly abiotic stress conditions [46,50].…”

“…The interplay between plant growth and stress signaling pathways has been reported [1,2]. As a regulatory hub linking primary metabolism, redox regulation and energy signaling [3], nicotinamide adenine dinucleotide (NAD) is presumably an important factor for stress resistance and for plant growth regulation under stress environments [4,5]. However, the relationship between NAD metabolism and plant stress responses is poorly understood.…”