Nicotinate phosphoribosyltransferase (NAPRT)

Nicotinate phosphoribosyltransferase (NAPRT) is the rate-limiting enzyme of the Preiss-Handler pathway, which converts nicotinic acid (niacin) into nicotinic acid mononucleotide (NaMN), a critical precursor for nicotinamide adenine dinucleotide (NAD+) (UniProt Q6XQN6). NAD+ is an essential cofactor for redox reactions and serves as a substrate for enzymes involved in DNA repair, such as PARPs, and sirtuins involved in cell signaling (PubMed: 28445455). In oncology, NAPRT is a significant metabolic target because many tumors, including those of the prostate, colon, and brain, exhibit NAPRT deficiency due to gene silencing or promoter hypermethylation (PubMed: 24651010). This deficiency renders cancer cells entirely dependent on the alternative NAMPT-mediated salvage pathway, creating a synthetic lethal vulnerability that can be exploited with NAMPT inhibitors (PubMed: 30104360). Conversely, in NAPRT-proficient tissues, the administration of exogenous nicotinic acid can provide a rescue mechanism against NAMPT inhibitor toxicity, thereby increasing the therapeutic window for treatment (PubMed: 20439754).

Other names

NAPRT1Nicotinate phosphoribosyltransferase 1Preiss-Handler pathway enzymeNAPRTase

NAPRT catalyzes the conversion of nicotinic acid (NA) and 5-phosphoribosyl-1-pyrophosphate (PRPP) to nicotinic acid mononucleotide (NaMN) and pyrophosphate, serving as the rate-limiting step in the Preiss-Handler pathway for NAD+ synthesis (UniProt Q6XQN6).