Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified. Here, we report the identification of Vacor as a substrate metabolized by the consecutive action of NAMPT and NMNAT2 into the NAD analog Vacor adenine dinucleotide (VAD). This leads to inhibition of both enzymes, as well as NAD-dependent dehydrogenases, thereby causing unprecedented rapid NAD depletion, glycolytic block, energy failure, and necrotic death of NMNAT2-proficient cancer cells. Conversely, lack of NMNAT2 expression confers complete resistance to Vacor. Remarkably, Vacor prompts VAD formation and growth suppression in NMNAT2-positive neuroblastoma and melanoma xenografts. Our data show the first evidence of harnessing the entire nicotinamide salvage pathway for antimetabolic strategies.

中文翻译：

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烟酰胺挽救途径的鉴定为抗代谢物的新毒化途径。

由于其在不同人类疾病中的治疗潜力，对烟酰胺腺嘌呤二核苷酸（NAD）代谢组调节的兴趣正获得极大的发展。然而，烟酰胺磷酸核糖基转移酶（NAMPT）抑制剂抑制烟酰胺挽救在肿瘤患者中没有定论，因为几种代谢途径绕过了直接在烟酰胺单核苷酸腺苷酸转移酶（NMNATs）上聚合的酶促阻滞，用于NAD合成。不幸的是，尚未鉴定出NMNAT抑制剂。在这里，我们报告的Vacor鉴定为通过NAMPT和NMNAT2连续作用代谢为NAD类似物Vacor腺嘌呤二核苷酸（VAD）的底物。这会导致两种酶以及NAD依赖性脱氢酶的抑制作用，从而导致空前的NAD快速消耗，糖酵解阻滞，能量衰竭和NMNAT2熟练癌细胞的坏死性死亡。相反，缺乏NMNAT2表达会赋予对Vacor完全抵抗力。值得注意的是，Vacor可以促进NMNAT2阳性神经母细胞瘤和黑色素瘤异种移植物中VAD的形成和生长抑制。我们的数据显示了利用整个烟酰胺挽救途径进行抗代谢策略的第一个证据。