The Nonoxidative Pentose Cycle, PRPP, and Poly(ADP-ribose) Polymerase

Another area of concern with this enhancement of the nonoxidative pentose cycle, such as with the enhancement of transketolase activity or ribose availability (either from exogenous nucleotides or ribose per se), is the potential for the provision of excessive NAD+ as a substrate for poly(ADP-ribose) polymerase (PARP). The PARPs are enzymes that can help in DNA repair but also can cause cell death by rapidly depleting cellular NAD+ and, secondarily, ATP (given that mitochondrial ATP production is dependent on the availability of NAD+ for multiple components of the electron transport chain). PARP uses NAD+ as a substrate for attaching ADP-ribose "polymers" to itself (auto-polyADP-ribosylation), after it binds to the DNA at a site of damage.

Researchers originally thought that supplementation with large doses of niacinamide (a form of vitamin B3, a.k.a. nicotinamide) would act as a PARP inhibitor and be useful in preventing damage and neuronal apoptosis, etc., following strokes. Niacinamide can, in vitro at least, bind to PARP and inhibit its activity somewhat, thereby, in theory, preventing some of the NAD+ depletion. I forget the details, but I think this approach didn't work at all. Also, there's in vivo research showing that niacinamide simply increases the production of NAD+ and actually increases PARP activity by that mechanism. Here's a striking example of that: (http://jn.nutrition.org/cgi/content/abstract/132/1/115). In that study, different bone marrow cells contained drastically different degrees of PARP activity and DNA damage, and this is exactly what one would expect from something, like niacinamide, that can increase PARP activity without some kind of buffering mechanism to prevent overactivation of PARP or some form of adenine nucleotide (ADP+AMP+ATP+Ado, etc.) depletion (secondary to willy-nilly production of NAD+ and ATP depletion). Another study found that the apparent anti-apoptotic effects of niacinamide were due to its effect of increasing PARP activity (http://www.nature.com/cdd/journal/v7/n3/abs/4400658a.html). Again, this and other studies with niacinamide give exactly the kinds of results one would expect to see, given the way PARP works in such a complex and cell-type and cell-context-specific manner.

The point of this is that niacinamide phosphoribosyltransferase uses PRPP to make NAD+, and so sources of exogenous ribose (or things, like the lipid-soluble thiamine prodrugs) could lead to inappropriate PARP activation by increasing PRPP levels and, as a result, NAD+ levels. There is some reason to think this would be less likely to occur with ribose, given that exogenous ribose would be bypassing ATP-consuming steps required for its production, that extra PRPP can also increase purine salvage, and that ribose also appears to increase ATP levels by activating glycolysis. But ribose could also increase de novo purine and pyrimidine synthesis in the face of something like folate deficiency and exacerbate DNA damage, leading to increases in PARP activity by that mechanism. It's interesting to note that purines and increases in ATP per se tend to decrease PARP activity. Hypoxanthine and other purines, including uric acid itself, can act as PARP inhibitors, and folate repletion tends to decrease PARP activity and preserve NAD+ levels by preventing the consumption of NAD+ by PARP. Here's an article showing a decrease in PARP activity and, consequently, an increase in NAD+ levels in response to folate/B12 repletion: (http://carcin.oxfordjournals.org/cgi/content/abstract/18/2/287). Here's one of many on purines inhibiting PARP activity: (http://www.fasebj.org/cgi/content/abstract/15/1/99).

So things like ischemia and folate/B12 deficiency increase DNA damage, DNA repair consumes a lot of ATP, ATP depletion increases PARP activity, PARP activity is enhanced in response to DNA damage, ischemia causes purine nucleotides to be exported from cells en masse, thereby increasing PARP activity, aberrantly-increased PARP activity can produce NAD+ depletion and ATP depletion, etc., in a vicious cycle. Thus, there's reason to think that some reasonable amount of folic acid and methylcobalamin (B12) supplementation would, in concert with purine nucleotide repletion, be a reasonable approach to prevent excessive PRPP-mediated increases in NAD+ levels, in response to exogenous ribose, that might lead to PARP-mediated ATP depletion, etc. It's noteworthy that a very large excess of purines can interfere with one-carbon metabolism (inhibiting S-adenosylhomocysteine hydrolase activity) and could increase PARP levels by that mechanism. I have a paper showing that in the liver, and I'll post the link to that later.