"Beneficial" Phosphate Sequestration and Buffering By Purines vs. Pyrimidines

This article is really interesting:

http://www.ncbi.nlm.nih.gov/pubmed/17324122

The authors discuss the effect that an elevation in ZMP (AICAribotide) has of sequestering phosphate and leading to ATP and adenine (and guanine) nucleotide depletion, much in the same way fructose-1-phosphate sequesters phosphate and produces purine depletion. ZMP acts as an AMP and therefore can't usually produce the "beneficial" effects, in terms of regulation of metabolism by many mechanisms, that AMP can. ZMP tends to inhibit AMP-activated regulatory mechanisms. I'm thinking that one reason there can be an obligatory requirement of exogenous purines for cell survival (at least under some circumstances), as shown in this article I'm linking to below, even when exogenous pyrimidines are provided, as in this study, might be that pyrimidine-derived ribose-1-phosphate wouldn't also yield a salvageable base (as in the case of purine-derived ribose) but would yield uracil and cytosine (which may be salvaged, as some authors have proposed, but generally probably are not). Those pyrimidine bases are metabolized by the propionate pathway, I think, ultimately via methylmalonyl-CoA mutase activity. But the purines would provide a source of bases, in addition to the ribose, that could buffer the loss of inorganic phosphate that would otherwise be lost due to ischemia or reperfusion-associated ATP depletion. So it would be a beneficial phosphate sequestration or would buffer phosphate levels. There would also be the buffering of hypoxanthine and so on, conceivably limiting catabolism of adenine- and guanine-based nucleotides. That would occur by separate mechanisms, to the extent that it would occur at all. Here's that article showing an adequate supply of intracellular purines to be a prerequisite for any cytoprotective effects of exogenous pyrimidines, such as uridine:

http://www.ncbi.nlm.nih.gov/pubmed/918825?dopt=Abstract

Also, I'm thinking that tiny reductions in ZMP, induced by repletion of intracellular total folates, could potentially produce large reductions in the loss of purines due to ischemia, for example, by preventing the formation of ZMP in the first place. I'd never considered this phosphate sequestration effect by ZMP in the folate-mediated increases in purine salvage, but it's possible the effect of ZMP only occurs at very high concentrations. I'd have to go look at all the intracellular AICAR information, and that's a tedious task. This effect, though, the sort of "leveraging" effect of AICAr (AICAriboside, the dephosphorylated form) and ZMP depletion, could occur with the reduced folates like (6S)-5-methyltetrahydrofolate (methylfolate) or leucovorin, given that they have bigger effects on reducing AICAR levels than folic acid. Using exogenous nucleotides with something like methylfolate would be a complex proposition, though, given the way exogenous nucleotides can lead to inhibition of S-adenosylhomocysteine hydrolase, etc.