NAD+ synthesis

NAD+ is one of the most abundant molecules in the human body, required for approximately 500 different enzymatic reactions and present at about three grams in the average person.

Though it was once considered a relatively stable molecule, NAD+ is now known to be in a constant state of synthesis, degradation, and recycling, not only in the cytoplasm but also within major organelles including the nucleus, Golgi and peroxisomes (Anderson et al., 2003). Recent advancements in high-resolution, high-sensitivity NAD+ metabolite tracing methods have revealed that the concentration and distribution of NAD+ and its metabolites are different depending on the cell compartment and change in response to physiological stimuli and cellular stress. NAD+ has two main pools, the “free” pool, and protein-associated, “bound” pool, and the ratio of these pools varies across different organelles, cell types, tissues, and even the age of individuals. There is also evidence that there are rapid, local fluctuations of NAD+ (Zhang et al., 2012).

With the exception of neurons, mammalian cells cannot import NAD+, so they must synthesize it either de novo by the kynurenine pathway from tryptophan (trp), or forms of vitamin-B3 such as nicotinamide (NAM) or nicotinic acid (NA). To maintain NAD+ levels, most NAD+ is recycled via salvage pathways rather than generated de novo.