Lesson 9: NAMPT

NAMPT (Nicotinamide Phosphoribosyltransferase) is a Protein Coding gene. Diseases associated with NAMPT include Aging and Gestational Diabetes. Among its related pathways are Circadian rythm related genes and NAD metabolism. Nicotinamide adenine dinucleotide (NAD) is a profoundly important cofactor in redox reactions. Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are key enzymes for NAD salvage biosynthesis pathway, which reciprocally synthesize NAD to supply the main source of NAD biosythesis. 

NAD, as an essential co-enzyme, mediates redox reactions in various metabolic pathways, including glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and serine biosynthesis. In addition, NAD functions as an important element for many signaling pathways by affecting the activity of several enzymes such as sirtuins (SIRTs) and poly(adenosine diphosphate [ADP]-ribose) polymerases (PARPs). Recent study revealed that NAD pool is increased in CRC tissues to reduce reactive oxygen species . The increased NAD also promotes the stemness maintenance and reduces the chemosensitivity of CRC cells . NAD anabolism can augment the aging-related secretory phenotype, which in turn promotes the occurrence of pancreatic tumors .

NAD can be synthesized through the de novo and salvage pathways. Even though most cells can synthesize NAD through the de novo pathway from tryptophan, the main source of NAD is supplied by salvage pathways that synthesize NAD from nicotinamide (NAM) or nicotinic acid (NA) as precursors because of its high efficiency. In the classical salvage pathway, NAMPT as a rate-limiting enzyme, convert NAM to nicotinamide mononucleotide (NMN), which is then adenylated to NAD by nicotinamide mononucleotide adenylyl transferase (NMNATs) . In the Preiss-Handler pathway, another kind of salvage pathway, nicotinate phosphoribosyltransferase (NAPRT) transforms NA to nicotinic acid mononucleotide (NAMN), which is then conjugated with ATP to generate NAD. NAMPT has been reported to be highly expressed in various tumors, such as gastric cancer, breast cancer, pancreatic cancer and prostate cancer, to promote tumor cell glycolysis, proliferation, survival, invasion, metastasis and chemotherapy resistance . In addition, NAPRT was also reported to be highly expressed in various cancers including ovarian cancer and pancreatic cancer. Silencing of NAPRT decreases NAD level and increases chemosensitivity of cancer cells. NAMPT and NAPRT have been reported to reciprocally synthesize NAD. As mentioned above, silencing of NAPRT or inhibition of NAPRT by 2-hydroxynicotinic acid increased the sensitivity to FK866, a specific inhibitor of NAMPT. More recently, selective cytotoxicity of FK866 to mesenchymal gastric cancer cells has also been reported due to loss of NAPRT expression.