Extensive regulation of nicotinate phosphoribosyltransferase (NAPRT) expression in human tissues and tumors

Duarte-Pereira, Sara; Pereira-Castro, Isabel; Silva, Sarah S.; Correia, Mariana Gonçalves; Neto, Célia; Costa, Luís Teixeira da; Amorim, António; Silva, Raquel M.

doi:10.18632/oncotarget.6538

Cited by 56 publications

(59 citation statements)

References 62 publications

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“…Although enzyme activity can be detected in most mouse tissues (86), Na acts as a more efficient precursor than Nam in mice liver, intestine, heart and kidney (87). Furthermore, Na is more efficient than Nam in raising NAD levels in cells exposed to oxidative stress (56,85,88).…”

Section: Nad Biosynthesis: the Enzymatic Functions Of Nampt And Naprtmentioning

confidence: 99%

“…NAPRT gene amplification in tumors correlated with NAPRT expression in matched normal tissues, suggesting a role for tissue context in determining which cancers amplify NAPRT (106). Duarte-Pereira et al in 2016 extensively studied expression of NAMPT and NAPRT in different tumor types and normal tissues (88). The initial step in that study was to evaluate NAPRT and NAMPT expression in a set of normal human tissues, highlighting a widespread expression for both genes.…”

Section: Nampt and Naprt In Tumorsmentioning

confidence: 99%

“…In tumors, while NAMPT was expressed at mRNA and protein levels in all samples analyzed, NAPRT protein levels were highly diverse, being undetected in several cases. Likewise, NAPRT protein is differentially expressed between cell lines, with markedly decreased expression in carcinoma cell lines MKN28 (gastric), 786-O (renal), HCT116 (colorectal), and in all leukemia cell lines tested (HL-60, NB4, and ML2) (88). Another paper highlighted a role for NAPRT, together with NAMPT, as negative prognostic marker in colorectal cancer, based on TCGA RNAsequencing data and protein tissue array (180).…”

Section: Nampt and Naprt In Tumorsmentioning

confidence: 99%

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

2020

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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.

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Section: Nad Biosynthesis: the Enzymatic Functions Of Nampt And Naprtmentioning

confidence: 99%

Section: Nampt and Naprt In Tumorsmentioning

confidence: 99%

Section: Nampt and Naprt In Tumorsmentioning

confidence: 99%

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

2020

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“…In normal cells, QPRT expression follows a tissue-specific distribution; more recent insights have revealed that QPRT expression is altered in some cancer cells (4)(5)(6)(7). The Preiss-Handler pathway converts nicotinic acid (NA) to NAMN through nicotinate phosphoribosyltransferase (NAPRT), an enzyme that is widely expressed in normal tissues but variably expressed in cancer cells (8)(9)(10)(11). NAMN is then converted to NAD + through the activity of NMNAT and NADS, as in the de novo pathway.…”

Section: Introductionmentioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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“…In fact, this method could permit the detection of new inhibitors of two enzymes, which are currently targets in cancer therapy (Cerna et al, 2012; Duarte-Pereira et al, 2016) – the human NAMPT (EC 2.4.2.12) and the nicotinate phosphoribosyltransferase (NaPRT) (EC 6.3.4.21), which use NAM and NA as substrates to convert them into NMN and nicotinic acid mononucleotide (NaMN), respectively. These enzymatic reactions produce a β- N -glycosidic bond with the pyridine nitrogen of both NAM and NA in presence of phosphoribosyl pyrophosphate (PRPP) and ATP.…”

Section: Discussionmentioning

confidence: 99%

Combined Whole-Cell High-Throughput Functional Screening for Identification of New Nicotinamidases/Pyrazinamidases in Metagenomic/Polygenomic Libraries

et al. 2016

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Nicotinamidases catalyze the hydrolysis of the amide bond in nicotinamide (NAM) to produce ammonia and nicotinic acid (NA). These enzymes are an essential component of the NAD+ salvage pathway and are implicated in the viability of several pathogenic organisms. Its absence in humans makes them a promising drug target. In addition, although they are key analytical biocatalysts for screening modulators in relevant biomedical enzymes, such as sirtuins and poly-ADP-ribosyltransferases, no commercial sources are available. Surprisingly, the finding of an affordable source of nicotinamidase from metagenomic libraries is hindered by the absence of a suitable and fast screening method. In this manuscript, we describe the development of two new whole-cell methods using the chemical property of one of the products formed in the enzymatic reaction (pyrazinoic or NA) to form colored complexes with stable iron salts, such as ammonium ferrous sulfate or sodium nitroprusside (SNP). After optimization of the assay conditions, a fosmid polygenomic expression library obtained from deep-sea mesophilic bacteria was screened, discovering several positive clones with the ammonium ferrous sulfate method. Their quantitative rescreening with the SNP method allowed the finding of the first nicotinamidase with balanced catalytic efficiency toward NAM (nicotinamidase activity) and pyrazinamide (pyrazinamidase activity). Its biochemical characterization has also made possible the development of the first high-throughput whole-cell method for prescreening of new nicotinamidase inhibitors by the naked eye, saving time and costs in the design of future antimicrobial and antiparasitic agents.

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Extensive regulation of nicotinate phosphoribosyltransferase (NAPRT) expression in human tissues and tumors

Cited by 56 publications

References 62 publications

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

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

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Combined Whole-Cell High-Throughput Functional Screening for Identification of New Nicotinamidases/Pyrazinamidases in Metagenomic/Polygenomic Libraries

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