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  • Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway.

Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway.

Cell metabolism (2020-03-05)
Igor Shats, Jason G Williams, Juan Liu, Mikhail V Makarov, Xiaoyue Wu, Fred B Lih, Leesa J Deterding, Chaemin Lim, Xiaojiang Xu, Thomas A Randall, Ethan Lee, Wenling Li, Wei Fan, Jian-Liang Li, Marina Sokolsky, Alexander V Kabanov, Leping Li, Marie E Migaud, Jason W Locasale, Xiaoling Li
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Nicotinamide-(amide-15N), 98 atom % 15N, 98% (CP)
Sigma-Aldrich
Nicotinic acid adenine dinucleotide sodium salt, ≥98%
Sigma-Aldrich
β-Nicotinamide adenine dinucleotide sodium salt
Sigma-Aldrich
β-Nicotinamide mononucleotide, ≥95% (HPLC)
Sigma-Aldrich
Nicotinic acid, ≥99.5% (HPLC)
Sigma-Aldrich
Tetramethylrhodamine ethyl ester perchlorate, suitable for fluorescence, ≥90% (HPCE)
Sigma-Aldrich
Nicotinamide, ≥99.5% (HPLC)
Sigma-Aldrich
Nicotinic acid mononucleotide
Sigma-Aldrich
Gentamicin solution, 50 mg/mL in deionized water, liquid, 0.1 μm filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Doxycycline hydrochloride
Sigma-Aldrich
MISSION® esiRNA, targeting human E2F1