Bacteria boost host NAD metabolism

摘要

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor in multiple redox reactions. It is also consumed by DNA repair enzymes poly-(adenosine diphosphate–ribose) polymerases (PARPs), protein deacylases sirtuins, and cyclic ADP ribose hydrolase CD38 to regulate many cellular processes, including energy metabolism, genome stability, and immune responses. Mammalian cells have multiple sources for NAD synthesis, including tryptophan (de novo pathway), nicotinic acid (NA, deamidated salvage pathway), and the ribosylated intermediates such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). However, the main route of NAD biosynthesis in most mammalian cells and tissues is believed to be the amidated salvage pathway, where nicotinamide (NAM) is converted to NAD by a two-step pathway with nicotinamide phosphoribosyl transferase (NAMPT) as the rate limiting enzyme. The steady-state levels of NAD are tightly balanced by consumption and biosynthesis, and deregulation of this homeostasis is associated with decreased cellular NAD levels in aging. Consequently, various therapeutic strategies for elevating NAD levels have been proposed, including supplementation with NAD precursors such as NAM, NR and NMN, activation of NAMPT, or inhibition of CD38, (reviewed in [1]). Conversely, since rapidly proliferating cancer cells have elevated metabolic demands, inhibition of NAD metabolism has been considered as a potential antineoplastic therapeutic strategy. Since NAMPT-mediated amidated biosynthesis is believed to be the main NAD biosynthesis pathway, these development efforts have largely been focused on NAMPT inhibitors [2].