ATP Consumption by Acute Increases in the Activities of Acyl-CoA Synthetases or Aminoacyl-tRNA Synthetases: Potential Relevance to Depression Research

In the abstract of this article [Capecchi et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9546959)], the authors discuss their finding that the administration, presumably intravenously, of either acetyl-L-carnitine (ALCAR) or propionyl-L-carnitine increased plasma concentrations of adenosine and ATP. I can't get the full text of that article, but I think that's relevant to an understanding of the apparent "plateauing" of (or even decreases in) the supposed mood-elevating effects of triacetyluridine at higher dosages [Jensen et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18540779)] and also to an understanding of the potential mechanisms by which high dosages of acetyl-L-carnitine might, in my opinion, worsen mood, even as lower dosages may produce a neutral effect or very, very slight beneficial effect, in that regard (though it seems that the main rationale for the use of acetyl-L-carnitine would be to increase beta-oxidation of fatty acids and to slightly augment mitochondrial functioning, by limiting the accumulation of fatty acyl-CoA thioesters that tend to inhibit the activities of mitochondrial enzymes, etc.). Although the authors of several articles have found some evidence that ALCAR elevates mood in elderly people, I wouldn't expect much in that regard. But hey, that's just my opinion. A little joke. There's a lot of research that shows the capacity of ethanol ingestion to elevate plasma acetate in humans [Puig and Fox, 1984: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC425250/)(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC425250/pdf/jcinvest00135-0276.pdf); (http://scholar.google.com/scholar?hl=en&q=acetate+ethanol+AMP+adenosine&btnG=Search&as_sdt=100000000)], and that effect of ethanol could produce transient mood elevation but also produce a worsening of mood in the "intermediate term" or longer term. In one explanation for that effect of ethanol, the oxidation of ethanol to acetaldehyde and to acetate increases the availability of free acetate (and increases plasma acetate and, concomitantly, increases the rate of urinary excretion of oxypurines, which are hypoxanthine and xanthine and urate/uric acid) (Puig and Fox, 1984) and thereby increases ATP consumption, as the free acetate serves as a substrate of acetyl-CoA synthetase and undergoes conversion into acetyl-CoA. The key point in many articles is that the rapid influx of acetate or another short-chain fatty acid (such as butyrate or one of the most-commonly-encountered ketones, beta-hydroxybutyrate and acetoacetate) or even longer-chain fatty acids, in theory, can consume enough ATP to significantly deplete the adenine nucleotide pools of cells and increase plasma urate, as ethanol can. Some of the older articles that discuss the capacity of acetate to induce ATP depletion, by increasing ATP turnover (consumption and also rephosphorylation of ADP and AMP and free adenosine and inosine and hypoxanthine) use the term "acetate thiokinase" to refer to acetyl-CoA synthetase [Ballard, 1972: (http://www.ncbi.nlm.nih.gov/pubmed/4558368)(http://www.ajcn.org/cgi/reprint/25/8/773.pdf)]. I cited this article by Vamecq et al., 2005 [Vamecq et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15713528)] in a past posting, and Vamecq et al. (2005) discussed the potential capacity for rapid increases in ketone or free-fatty-acid availability to increase ATP consumption and thereby, potentially, contribute to the supposed therapeutic effects of "ketogenic" diets (see p. 13, Fig. 4, along with other parts of the article). It's interesting that Ballard (1972) cited research (see column 1, p. 775, refs. 22 and 23) showing that the inhibition of TCA cycle enzymes or, by implication, inhibition of respiration per se, given that decreases in ADP availbility or in the availability of inorganic phosphate exacerbated the effect, had been shown to increase the accumulation of free acetate in in vitro or ex vivo experiments. That could, presumably, occur because a decrease in ATP availability would be expected to decrease the rate of acetyl-CoA formation. It's interesting that phosphate can, evidently, limit the accumulation of free acetate, presumably by vitrtue of its inhibitory effect on adenosine deaminase activity (thereby limiting purine degradation and loss from the cells) [not a good search, but: (http://scholar.google.com/scholar?hl=en&q=phosphate+inorganic+%22adenosine+deaminase%22+OR+%22Adenylic+Acid+Deaminase%22&btnG=Search&as_sdt=100000000&as_ylo=&as_vis=0)]. Anyway, the point is that the deacetylation (esterolysis, etc.) of triacetyluridine may yield significant amounts of acetate, and this might mean that higher dosages could begin to cause meaningful increases in ATP consumption, in my opinion. At lower dosages, the acetate-mediated elevations in extracellular adenosine could contribute to the supposed mood-elevating effects of triacetyluridine. In my experience, the "beneficial" effects of triacetyluridine are not nearly as significant when the triacetyluridine is taken in the absence of oral adenosine monophosphate or ATP disodium, etc. Those supplements haven't been proven to produce mood-elevating effects, however, and could worsen the moods of some people, and one would, obviously, want to discuss this type of thing with one's doctor. It's interesting that 2'-O-acetyl-ADP-ribose and 3'-O-acetyl-ADP ribose (and also ADP that contains di-O-acetylated ribose) are produced endogenously (http://scholar.google.com/scholar?hl=en&q=ADP-ribose+acetyl+ribose&btnG=Search&as_sdt=100000000&as_ylo=&as_vis=0). Maybe that endogenous formation of acetylated ribose (triacetyluridine is 2', 3',5'-tri-O-acetyluridine) allows for the formation of some "ribosyl" adducts of lysine or other amino acid residues on proteins to occur spontaneously and limit the potential for O-acetylated nucleoside prodrugs to become antigenic, as discussed in past postings. Another thing is that some researchers have suggested that the rapid influx of some free amino acids could cause ATP depletion by increasing the aminoacyl-tRNA synthetase-dependent consumption of ATP, in the formation of aminoacyl-tRNAs. It's conceivable that the supposed advantages of the use of L-glutamine as an energy substrate are partially a result of the (presumably) lower activities of enzyme(s) that exhibit glutaminyl-tRNA synthetase activity, in comparison to the activities of other aminoacyl-tRNA synthetase enzymes. There could also, conceivably, be a lag time, of some length of hours or days, before some kind of steady-state increases in the pool of glutaminyl-tRNA occur, in response to the administration of exogenous L-glutamine (http://scholar.google.com/scholar?hl=en&q=glutaminyl-tRNA+eukaryotic+OR+human&btnG=Search&as_sdt=100000000&as_ylo=&as_vis=0). The full ATP-buffering effects that glutamine might, conceivably, produce might not occur immediately, given the potential for glutaminyl-tRNA synthetase enzymes to consume ATP. But I think that that would be much more likely to be an effect that amino acids other than glutamine would have. It's interesting that some or maybe all aminoacyl-tRNA synthetases are zinc dependent, and some researchers have investigated the potential significance of the zinc-mediated activation of aminoacyl-tRNA synthetase enzymes and consequent increases in ATP turnover or depletion [see Plateu et al., 1981: (http://scholar.google.com/scholar?hl=en&q=aminoacyl-tRNA+synthetase+ATP+depletion+OR+consumption&btnG=Search&as_sdt=100000000&as_ylo=&as_vis=0)].