Shats Igor, Williams Jason G, Liu Juan, Makarov Mikhail V, Wu Xiaoyue, Lih Fred B, Deterding Leesa J, Lim Chaemin, Xu Xiaojiang, Randall Thomas A, Lee Ethan, Li Wenling, Fan Wei, Li Jian-Liang, Sokolsky Marina, Kabanov Alexander V, Li Leping, Migaud Marie E, Locasale Jason W, Li Xiaoling
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Mass Spectrometry Research and Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Cell Metab. 2020 Mar 3;31(3):564-579.e7. doi: 10.1016/j.cmet.2020.02.001.
Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in metabolism, DNA repair, and aging. However, how NAD metabolism is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer resistance to inhibitors of NAMPT, the rate-limiting enzyme in the amidated NAD salvage pathway, in cancer cells and xenograft tumors. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. Using stable isotope tracing and microbiota-depleted mice, we demonstrate that this bacteria-mediated deamidation contributes substantially to the NAD-boosting effect of oral nicotinamide and nicotinamide riboside supplementation in several tissues. Collectively, our findings reveal an important role of bacteria-enabled deamidated pathway in host NAD metabolism.
烟酰胺腺嘌呤二核苷酸（NAD）是所有细胞类型中数百种代谢反应的辅助因子，在新陈代谢、DNA修复和衰老过程中发挥着至关重要的作用。然而，NAD代谢如何受到环境影响仍不清楚。在此，我们报告了细菌与哺乳动物细胞之间一种意想不到的跨物种合作，其中细菌有助于宿主NAD的生物合成。细菌赋予癌细胞和异种移植肿瘤对NAMPT抑制剂的抗性，NAMPT是酰胺化NAD补救途径中的限速酶。从机制上讲，一种将烟酰胺转化为烟酸（替代脱酰胺NAD补救途径中的前体）的微生物烟酰胺酶（PncA）对于这种保护作用是必要且充分的。使用稳定同位素示踪和无菌小鼠，我们证明这种细菌介导的脱酰胺作用在很大程度上有助于口服烟酰胺和烟酰胺核糖补充剂在多个组织中提高NAD的效果。总的来说，我们的研究结果揭示了细菌介导的脱酰胺途径在宿主NAD代谢中的重要作用。
