The ways to Increase NAD Levels naturally

The main ways to synthesize NAD+

The synthesis of NAD+ is divided into salvage pathway, de novo synthesis pathway and Preiss-handler pathway according to different synthetic raw materials.

a) De novo synthesis pathway: tryptophan (Trp) is converted to quinolinic acid (QA), and then converted to NAMN by quinolinic acid-phosphoribosyl transferase (QPRT). NAMN is converted into NAAD, and finally NAD+ is catalyzed by NAD+ synthetase (NADS).

b) P-H synthesis pathway (also called NA salvage pathway): Niacin (NA) synthesizes NAD+ through NAPRT, NMNAT, and NADS (NAD synthetase).

c) Remedial synthesis pathway (also called NR remedial pathway): Nicotinamide ribose (NR) or nicotinamide (NAM) is synthesized through NRK (nicotinamide riboside kinase) or NAMPT, NMNAT to synthesize nicotinamide mononucleotide (NMN), NMN NAD+ is synthesized by NMNAT1-3 enzyme.

In addition, nicotinic acid nucleoside (NAR) can also produce NAMN through NRK catalysis, and then through the enzymatic reaction in 1 to synthesize NAD+.

 

 

 

 

 

 

 

PNP: purine nucleoside phosphorylase; NRK: nicotinamide riboside kinase; QPRT: quinolinate phosphoribosyl transferase NAPRT: nicotinic acid phosphoribosyl transferase; NAMPT: nicotinamide phosphoribosyl transferase; NMNAT: nicotinamide mononuclear Adenylyltransferase

The synthesis of NAD+ in vivo has tissue heterogeneity:

 

 

 

 

 

 

 

 

 

NAD(H) concentration in various tissues and organs of mammals

The preference of mammalian tissues and organs for NAD+ raw materials is mainly related to the tissue specificity of the NAD synthase expressed by them.

The liver uses tryptophan to synthesize NAD+ de novo. During the synthesis-use NAD+ cycle, a large amount of NAM (niacinamide) is secreted, and these niacinamides can be taken up and utilized by other organs and tissues along with the circulation.

The exchange of endogenous niacin (NA) between blood and tissues and organs is rarely very slow, and most tissues and organs do not rely on NA in the blood to synthesize NAD.

Tissues other than the liver rely on NAM transported by the circulatory system to synthesize NAD. Skeletal muscle is the tissue with the lowest efficiency of ingesting NAM to synthesize NAD+, and the small intestine and spleen are the tissues with the highest efficiency of using NAM to synthesize NAD+.

 

 

 

 

 

 

 

 

 

Expression of various NAD(H) synthetase enzymes in various tissues and organs of mammals.

How does NMN (Nicotinamide Mononucleotide) enter the cell?

 

 

 

 

 

 

 

 

Nicotinamide Mononucleotide NMN has a membrane transporter on the surface of some cells, which can directly transfer NMN into the cell, so there are two ways for NMN to enter the cell:

① Enter cells directly through transporters: At the beginning of 2019, a paper on nature metabolism confirmed this idea. The article found that there is a NMN-specific transporter in the small intestine of mice, called Slc12a8, which is an amino acid and polyamine transporter. It has a high selectivity for NMN and does not transport NaMN, which is very similar in structure to NMN.

②The CD73 on the cell membrane surface is dephosphorylated into NR (by balancing the nucleoside transporter ENTs) and enters the cell, and then it is catalyzed by the cytoplasmic NRK enzyme to NMN, which enters the mitochondria and is used (the mitochondria have no NRK).

NAM is not only the precursor of NMN, but also the product of NAD+ hydrolyzed by CD38 through the NADase activity depletion pathway. Therefore, the synthesis, utilization, and regeneration of NAD+ is a

Involve the intracellular and extracellular circulation.

NMN/NR→NAD+→NAM→NMN