NAMPT in Regulated NAD Biosynthesis and its Pivotal Role in Human Metabolism

Burgos, Emmanuel S.

doi:10.2174/092986711795590101

Cited by 64 publications

(53 citation statements)

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“…NAMPT catalyzes the ratelimiting step of nicotinamide adenine dinucleotide (NAD ? ) synthesis and controls cell survival and inflammation [50,51]. Exogenous PBEF1/NAMPT/Visfatin has proangiogenic activity, regulates endothelial IL6 production through Stat3 in vitro [52] and can induce the mTOR pathway in HUVEC cells [53].…”

Section: Discussionmentioning

confidence: 99%

The experimental renal cell carcinoma model in the chick embryo

et al. 2012

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The clear cell subtype of renal carcinoma (CCRCC) is highly vascularized and despite a slow progression rate, it is potentially a highly aggressive tumor. Although a doubling of median progression-free survival in CCRCC patients treated by targeted therapies has been observed, the fact that tumors escape after anti-VEGF treatment suggests alternative pathways. The chick chorioallantoic membrane (CAM) is a well-established model, which allows in vivo studies of tumor angiogenesis and the testing of anti-angiogenic molecules. However, only a few data exist on CCRCC grafted onto CAM. We aimed to validate herein the CAM as a suitable model for studying the development of CCRCC and the interactions with the surrounding stroma. Our study uses both CCRCC cell lines and fresh tumor samples after surgical resection. We demonstrate that in both cases CCRCC can be grafted onto the CAM, to survive and to induce an angiogenic process. We further provide insights into the transcriptional regulation of the model by performing a differential analysis of tumor-derived and stroma-derived transcripts.

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Section: Discussionmentioning

confidence: 99%

The experimental renal cell carcinoma model in the chick embryo

et al. 2012

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“…Mild lymphopenia was observed in early trials of NAMPT inhibitors, but thrombocytopenia was the dose limiting toxicity 123 . Limited clinical efficacy has been observed thus far, although work is ongoing to develop more potent compounds and define those patients most likely to benefit from NAMPT inhibition 124 .…”

Section: --Deoxyglucose (2dg) Is An Inhibitor Of Glucose Metabolism mentioning

confidence: 99%

Targeting cancer metabolism: a therapeutic window opens

Heiden

2011

Nat Rev Drug Discov

1,266

1,076

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PrefaceGenetic driver events in cancer activate signaling pathways that alter cell metabolism. Clinical evidence has linked metabolism with cancer outcomes.Together, this has raised interest in targeting metabolic enzymes for cancer therapy, but also concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies target the specific metabolic needs of cancer cells and remain effective agents used in the clinic today. Research to understand how changes in cell metabolism promote tumor growth has accelerated in recent years. This has refocused efforts on targeting metabolic dependencies of cancer cells, an approach with the potential to have a major impact on patient care.

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“…Parameters such as K m , K d and K i are given for a better illustration of these similarities. 11,20 …”

Section: Figmentioning

confidence: 99%

“…NAMPT catalyzes the rate limiting step in NAD salvage, a documented role in human metabolism. 11 It is linked to the function of sirtuins through modulation of NAD synthesis. 12 NAMPT inhibition causes reduced levels of NAD and induces premature senescence, while its over-expression inhibits cell death.…”

Section: Introductionmentioning

confidence: 99%

Recycling Nicotinamide. The Transition-State Structure of Human Nicotinamide Phosphoribosyltransferase

2013

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Human nicotinamide phosphoribosyltransferase (NAMPT) replenishes the NAD pool and controls the activities of sirtuins (SIRT), mono- and poly-(ADP-ribose) polymerases (PARP) and NAD nucleosidase (CD38). The nature of the enzymatic transition-state (TS) is central to understanding the function of NAMPT. We determined the TS structure for pyrophosphorolysis of nicotinamide mononucleotide (NMN) by kinetic isotope effects (KIEs). With the natural substrates, NMN and pyrophosphate (PPi), the intrinsic KIEs of [1′-14C], [1-15N], [1′-3H] and [2′-3H] are 1.047, 1.029, 1.154 and 1.093, respectively. A unique quantum computational approach was used for TS analysis that included structural elements of the catalytic site. Without constraints (e.g. imposed torsion angles), the theoretical and experimental data are in good agreement. The quantum-mechanical calculations incorporated a crucial catalytic site residue (D313), two magnesium atoms and coordinated water molecules. The transition state model predicts primary 14C, α-secondary 3H, β-secondary 3H and primary 15N KIE close to the experimental values. The analysis reveals significant ribocation character at the TS. The attacking PPi nucleophile is weakly interacting (rC-O = 2.60 Å) and the N-ribosidic C1′-N bond is highly elongated at the TS (rC-N = 2.35 Å), consistent with an ANDN mechanism. Together with the crystal structure of the NMN•PPi•Mg2•enzyme complex, the reaction coordinate is defined. The enzyme holds the nucleophile and leaving group in relatively fixed positions to create a reaction coordinate with C1′-anomeric migration from nicotinamide to the PPi. The transition state is reached by a 0.85 Å migration of C1′.

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NAMPT in Regulated NAD Biosynthesis and its Pivotal Role in Human Metabolism

Cited by 64 publications

References 0 publications

The experimental renal cell carcinoma model in the chick embryo

The experimental renal cell carcinoma model in the chick embryo

Targeting cancer metabolism: a therapeutic window opens

Recycling Nicotinamide. The Transition-State Structure of Human Nicotinamide Phosphoribosyltransferase

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