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

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.

Keywords: DAMPs; NAMPT; NAPRT; TLRs; cancer; inflammation; metabolism; signaling.

Figure 1

Intra/extra NAD interconnections and NAD-metabolizing enzymes. Schematic representation of the network of NAD-metabolizing cell surface and intracellular enzymes and their products. Several NAD precursors derived from diet can be internalized to generate iNAD, via NBE activities, to support energy metabolism, signaling, and other biological processes through the activities of intracellular NAD-consuming enzymes (PARPs and Sirtuins). These enzymes release Nam that, in turn, via NAMPT-dependent salvage pathway, support NAD production. Once in the extracellular space because of secretion/leakage, via Cx43, or because of direct extracellular synthesis from precursors (not confirmed), eNAD can function by binding purinergic receptors (P2Y, P2X), an event that leads to intracellular signaling and inflammatory conditions. Alternatively, eNAD can also be metabolized by a series of ecto-enzymes of the cell surface (CD38/CD157, ARTs, CD73, ENPP1) generating different metabolites (cADPR, ADPR, and NAADP) involved mainly in Ca²⁺-signaling. The end product of the reaction, adenosine, can modify signal transduction by acting on P1 purinergic receptors, generally leading to immunosuppression. In the square brackets are indicated the range of iNAD [200–500 μM] or eNAD [100–500 nM]. Trp, tryptophan; Nam, nicotinamide; NR, nicotinamide riboside; Na, nicotinic acid; NBEs, NAD-biosynthetic enzymes; NAMPT, nicotinamide phosphoribosyltransferase; ARTs, mono adenosine diphosphate (ADP)-ribose transferases; PARPs, poly ADP-ribose polymerases; Cx43, connexin 43; ADPR, ADP ribose; cADPR, cyclic ADP ribose; NAADP, nicotinic acid adenine dinucleotide phosphate; NMN, nicotinamide mononucleotide; ADO, adenosine; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterases.

Figure 2

NAD biosynthetic pathways. NAD can be synthetized de novo starting from Trp (pink rectangle), or through salvage routes from Nam and NR (green rectangle), or metabolizing Na in the Preiss-Handler pathway (light blue rectangle). NAD-precursors are indicated in the blue ovals. The rate-limiting enzymes of each biosynthetic pathway are indicated in red, the other enzymes involved in the reactions in orange. For NAMPT and NAPRT crystal structures are shown. NAD synthesized from Nam via NAMPT is in turn used by NAD-consuming enzyme activities that release Nam, making it available for continuous NAD regeneration. NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinate phosphoribosyltransferase; NRK, nicotinamide riboside kinase; QPRT, quinolinate phosphoribosyltransferase; NMNATs, nicotinamide mononucleotide adenylltransferases; NADS, NAD synthase; Nam, nicotinamide; NR, nicotinamide riboside; Na, nicotinic acid; Trp, tryptophan; QA, quinolinic acid; NMN, nicotinamide mononucleotide; NAMN, nicotinate mononucleotide; NAAD, nicotinate adenine dinucleotide; NADase, NAD-glycohydrolase; ARTs, mono adenosine diphosphate (ADP)-ribose transferases; PARPs, poly ADP-ribose polymerases.

Figure 3

Extracellular functions of NAMPT and NAPRT. iNAMPT and iNAPRT are involved in NAD generation inside of cells, but can be also secreted, through unknown mechanisms, in the extracellular space due to cellular stresses (damage/inflammation/pathological conditions). Extracellularly, they can act as adipocytokine/DAMP binding to TLR4 and triggering intracellular signaling promoting differentiation/polarization of myeloid cells, activation of inflammosome, secretion of pro or anti-inflammatory cytokines. The final outcome depends on the cellular context, for example in tumors eNAMPT creates an immunosuppressive microenvironment, favoring cancer progression, while eNAPRT in sepsis amplifies the inflammatory response. TLR4, Toll-like receptor 4; MD2, myeloid differentiation 2; MYD88, myeloid differentiation primary response gene 88; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinate phosphoribosyltransferase; NBEs, NAD-biosynthetic enzymes; Nam, nicotinamide; Na, nicotinic acid; DAMP, damage-associated molecular pattern; PARPs, poly ADP-ribose polymerases.