This is an interesting article [Jankowski et al., 2009: (http://www.brjpharmacol.org/view/0/earlyView.html)], and the authors discuss the fact that dinucleotide polyphosphates (DNPP) are made endogenously and stored in platelets, adrenal chromaffin cells, and also neurons in the brain. The general formula for a DNPP is N-p(x)-N, where N = adenosine, guanosine, uridine, etc., and x = 2 to 7 phosphates linking two 5'-carbons of the ribose moieties of the nucleotides. Some common examples are diadenosine tetraphosphate (Ap4A) and Ap5A, Up4A (U = uridine), etc. That article doesn't discuss that much about their biosynthesis, but it turns out they're formed by aminoacyl-tRNA synthetases, just as the isoprenoid-based nucleotide polyphosphates are (see recent posting). They can also be formed by Ap4A phosphorylases, luciferase enzymes, and guanylyltransferases [Schluter et al., 1998: (http://www.pubmedcentral.nih.gov/picrender.fcgi?doi=10.1172/JCI119882&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9449703)]. The different DNPP's have agonist and antagonist effects, at low concentrations, on purinergic receptors, and the article by Jankowski et al. (2009) catalogues a lot of those effects on platelet aggregation, etc. They're apparently degraded fairly slowly by various hydrolase enzymes.
So I guess to understand the interactions of cholesterol and nucleotide metabolism, one should read about the regulation of aminoacyl-tRNA synthetases. That's bizarre, but it seems interesting. It looks like the DNPP's have both "good" and "bad" effects, as one might expect, and it sounds like the concentrations can be fairly high, in the millimolar range, in vesicles in neurons or in platelet secretory granules. They basically are thought to act locally, the way purines and other nucleotides act on purinergic receptors. The plasma concentrations of different diadenosine oligophosphates/polyphosphates are 0.18 to 0.89 uM, but Jankowski et al. (2009) think that they may act locally on platelets and influence platelet aggregation under some circumstances. It sounds like one effect might be on phosphate homeostasis, as the authors of that article on isopentenyl-ATP derivatives were implying and suggesting. It seems like there may be a tendency to focus a lot on the effects of DNPP's on purinergic receptors, but it sounds like the intracellular effects might be more important. I haven't read much of anything on this topic yet, and there's probably some research about that type of thing. Maybe they regulate cholesterol metabolism or interfere with nucleotide transport. Some genetic mutations that affect nucleotide transport can cause mtDNA depletion, and then there are the more short-term effects (of DNPP's), such as on respiration, that could potentially occur via the inhibition of the adenine nucleotide translocase transporter. I wonder if there's anything on mRNA stability or something like that or on transcription. Presumably there are all sorts of potential pathological effects, but I actually don't know anything about the mechanisms governing the intracellular transport of DNPP's. I also don't know what factors regulate their formation by the aminoacyl-tRNA synthetases or by other enzymes. Schluter et al. (1998) say that the half lives of various DNPP's range from 49 to 69 minutes, and those are much longer than the half-lives of purines. The half-life of plasma adenosine is about 0.5 to 1.5 seconds.
It's interesting that Schluter et al. (1998) say that the aminoacyl-tRNA synthetases transfer the AMP of an aminoacyl-AMP to a nucleotide diphosphate or triphosphate and form the DNPP and also release an amino acid. I wonder if there's some kind of specificity to the aminoacyl-tRNAs that form specific DNPP's. If there were (I have no idea if there is), then that could explain some of these strange effects of different amino acids. That could explain some of the puzzling effects of glutamine, such as its antiapoptotic effects. For example, glutaminyl-tRNA synthetase [Ko et al., 2001: (http://www.jbc.org/cgi/content/full/276/8/6030)(http://www.ncbi.nlm.nih.gov/pubmed/11096076?dopt=Abstract)] produces antiapoptotic effects, in a glutamine-dependent manner, by obscure mechanisms. Ko et al. (2001) discuss some of the mechanisms by which glutaminyl-tRNA synthetase may contribute to the supposed antiapoptotic effects of glutamine. Maybe there's some intermediary influence of glutaminyl-tRNA-derived DNPP's in the antiapoptotic effects of glutamine, under some circumstances. I mean, maybe the DNPP formation is facilitated in some way by protein-protein interactions of glutaminyl-tRNA synthetase and some other protein [even the apoptosis signal-regulating kinase 1, discussed by Ko et al. (2001), that interacts with glutaminyl-tRNA synthetase, etc.]. Those are crude ideas, but it's interesting. The article by Ko et al. (2001) discusses the effects of glutamine on various mitogen-activated protein kinase pathways.
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