Role of thiamine in NAD+ synthesis from Niacin and Nicotinamide

Highlights

• Thiamine deficiency may have significant impact on the ability of the cells to salvage NAM for synthesis of NAD.

• People taking high doses of Niacin to boost NAD may also benefit from improving thiamine status.

• People concerned about NAD+ should pay attention to thiamine as well.

• Hypothesis: Taking high doses of Niacin or NAM may tax the body in subjects with suboptimal thiamine status.

NAD is primarily made from NAM via salvage pathway and that needs PRPP

I recently found that NAD synthesis from Niacin or Nicotinamide (NAM) depends on availability of PRPP (Phosphoribosyl pyrophosphate) and the synthesis of NAD from NAM is the main internal source:

In mammalian cells, the principle contributor to NAD+ synthesis is the nicotinamide (NAM) salvage pathway involving sequential actions of nicotinamide phosphoribosyltransferase (NAMPT) and NMN adenylyltransferases (NMNAT1-3).

NAMPT forms NMN and pyrophosphate (PP) from NAM (generated by sirtuins and PARPs) and α-D-5-phosphoribosyl-1-pyrophosphate (PRPP). In turn, NMNAT1-3 produce NAD+ from NMN and ATP. (R2)

Availability of PRPP affects salvage rate of NAM - PRPP increases affinity of the NAMPT enzyme for NAM:

When PRPP binds the phosphorylated enzyme the affinity for NAM increases and promotes the conversion of NAM to NNM. (R5)

PRPP is made from Ribose

PRPP is synthesized from Ribose-5-phosphate and ATP by the enzyme PRPS1, which uses Mg2+ as a cofactor. (R3)

Ribose availability depends on thiamine status

Ribose is made in the Pentose Phosphate pathway, actually in both parts of it - oxidative and non-oxidative:

The fractional rate of de novo ribose synthesis from glucose is decreased several fold 2 to 4 days after removal of thiamine from the culture medium. (R4)

and from the same paper:

The fractional synthetic rate is reduced in thiamine-depleted TRMA cells. In addition, the fraction of ribose derived from the preferred nonoxidative (transketolase/transaldolase) portion of the pentose phosphate pathway is reduced in favor of the oxidative pentose pathway branch (via G6PDH). (R4)

Synthesis of NAD from NMN and NR is not affected

Since NMN and NR already contain ribose part, synthesis of NAD from them is not affected directly by low function of the TKT enzyme and ribose synthesis.

Only synthesis of NAD from Niacin and Niacinamide have this dependency on PRPP and indirectly on thiamine status.