Uridine in Relation to Glycolysis and Gluconeogenesis

This article lends some credence to the results of cell-culture studies that suggest that neuroprotection by uridine (and also by purines) is *partially* mediated by the nucleoside phosphorylase (uridine phosphorylase or purine nucleoside phosphorylase) mediated liberation of ribose-1-phosphate from the nucleotide (or by some similar effect of facilitating glycolysis, rather than only by elevating the pyrimidine pool):

http://www.ncbi.nlm.nih.gov/pubmed/16330000 (Garcia et al., 2005)

I linked to that article previously, and it's a really complicated article. I didn't understand it the first time I read it, but the authors found that uridine, derived from triacetyluridine (PN401/RG2133, a uridine prodrug that is deacetylated by esterase enzymes, in the intestinal tract and probably elsewhere, and elevates the plasma uridine concentration substantially), produces neuroprotection without actually leading to net elevations in the overall concentrations of pyrimidine nucleotides in the brain.

The article is confusing at first because, at first glance, the authors appear to be saying that this ten-to-fifteenfold elevation in plasma uridine [or more than that in rodents, in which the major circulating pyrimidine is cytidine and not uridine (uridine is the major plasma pyrimidine nucleotide in humans)] is not elevating the uridine levels in the brain. But that's not what the data show. The authors are just showing that the uridine that reaches the brain is probably being converted into uracil and ribose-1-phosphate by uridine phosphorylase (or, after first being converted into cytidine nucleotides, into cytosine and its ribose moiety). They're not saying there's no pyrimidine elevation, but they're showing that, particularly under conditions of metabolic stress (complex IV inhibition), there's reason to think the activities of enzymes that catabolize pyrimidines may be increased.

One way of explaining it is in terms of the reversibility of uridine phosphorylase. Some of these articles suggest that uracil can be salvaged in the brains of rats and that the reaction can favor uridine, and not uracil, formation under some circumstances (and I'm just saying that, assuming this is true, the formation of uracil would probably be favored during something like azide-induced complex IV inhibition):

http://www.ncbi.nlm.nih.gov/pubmed/9133638 (Giorgelli et al, 1997)

http://www.ncbi.nlm.nih.gov/pubmed/10699492 (Mascia et al., 2000)

http://www.ncbi.nlm.nih.gov/pubmed/9795240 (Cappiello et al., 1998)

http://www.ncbi.nlm.nih.gov/pubmed/16519676 (Tozzi et al., 2006)

http://www.ncbi.nlm.nih.gov/pubmed/16893570 (Camici et al., 2006)

This article shows that the degradation of nucleotides would be expected to increase in response to hypoxia and ischemia:
http://www.ncbi.nlm.nih.gov/pubmed/11782482 (Barsotti et al., 2002)

I also think that the contribution to neuroprotection of uracil-derived beta-alanine shouldn't necessarily be dismissed. Even though this article talks about the way methylmalonate semialdehyde dehydrogenase, an enzyme that produces acetyl-CoA from malonate semialdehyde (derived from beta-alanine, from uracil) and also propionyl-CoA from either (R)-methylmalonate semialdehyde or (S)-methylmalonate semialdehyde, is inhibited by NADH and participates in gluconeogenesis (the elevated cytoplasmic NADH/NAD+ ratio that would be expected to occur in response to complex IV inhibition by azide and that would favor the entry of ribose-1-phosphate into glycolytic pathways would also tend to decrease the activity of methylmalonate semialdehyde dehydrogenase and other gluconeogenic enzymes), there are many things that are not known about the regulation of gluconeogenesis and glycolysis under conditions of metabolic stress. The authors of this article discuss the way people with propionic aciduria can't ingest lots of pyrimidines (though most foods have no bioavailable nucleotides):

http://www.jbc.org/cgi/content/abstract/264/25/14965 (Gary Goodwin et al., 1989)

Propionic acidemia certainly causes neurological symptoms, and it's possible that the entry of ribose-1-phosphate into the nonoxidative pentose cycle works in concert with the propionate pathways to support ATP levels and neuroprotection, as in response to triacetyluridine.