Replenishment of the cellular NAD+ pool

Because NAD+ molecules are continuously consumed in the body, the cells are dependent on a constant supply in order to fulfill their functions. As a universal molecule of all organisms, NAD+ is ingested with food, but it cannot usually be absorbed by the cells. Instead, it must first be converted into smaller uncharged molecules in the small intestine in order to pass through the intestinal barrier and be distributed throughout the body via the bloodstream. The body‘s cells therefore produce the vital molecule themselves from the NAD metabolites, but also from the essential amino acid trypto-phan. The new formation of NAD+ from tryptophan is particularly relevant in the liver, kidneys, brain and in certain immune cells and leads in various reaction steps to kynurenine and quinolinic acid and further to NAD+ .

However, NAD+ formation via the side pathway of the kynurenine pathway is not particularly efficient, as it competes with the biosynthesis of the happiness hormone serotonin and the sleep hormone melatonin from tryptophan, as well as with protein biosynthesis.3 Most tissue cells recycle the majority of NAD+ from nicotinamide (NAM), which is formed as a by-product of all NAD+-consuming enzymes. In addition, NAM and other metabolites of NAD+ metabolism such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) from food are recycled via this “salvage” pathway. The eye of the needle is the enzyme NAMPT (nicotinamide phospho-ribosyltransferase), which is produced in the rhythm of the internal clock. It catalyzes the first reaction step from NAM to NMN and is produced in greater quantities when there is an increased need for NAD+ and cellular stress such as starvation, sport or immune cell activation. Nicotinic acid, which is found in many foods and was originally called niacin* to distinguish it from the addictive drug nicotine, is the starting substance for another NAD+ synthesis pathway. It is named the Preiss-Handler pathway after its discoverers. The de novo synthesis pathway from tryptophan also leads to this pathway. Important key enzymes of all three NAD+ synthesis pathways are the NMNATs (nicotinamide mononucleotide adenylyltransferases).  In nerve cells, in which according to the human protein atlas comparatively few NAMPT enzymes are formed, NMNAT enzymes appear to ensure the NAD+ supply via the other two synthesis pathways and have a neuroprotective effect. In addition to the body cells, intestinal bacteria, which break down fiber that is indigestible for humans, also help to replenish the NAD+ stores. They not only produce NAD+ themselves, but also channel the host‘s NAD+ precursors via alternative routes, so that the host is better equipped to deal with a failure of one of the biosynthetic pathways.