Down in the Valley

Way down in the valley,
Down the swirling steps,
Through the spinning rapids,
Among the sparkling stones,
On the glitter-gumdrop river,
You rolled along the currents
And met me where the water
Slows and spreads across the plain.
We watched,
Together,
As the jagged
Canyon
City
Came tumbling
Down
Around us
And crumbled in the desert.
When the sun
Was setting,
The river
Flowed
Up the crystal wall
Waterfall,
Over the iron
Cliffs, past the
Places where the
Animals
Roam and run,
And
Your eyes
Are
Roaring
Lions
That
Let us
Ride
Up and over
The red clay
Gym-classs
Springboard
Country.

Doming in a Ferryl-to-Ring Charge Transfer Complex

It's noteworthy that I attempted to showcase the "bright magenta" or "bright fuchsia" color, in the positive-phase lobes of the atomic orbitals and molecular orbitals (MOs), but the program only allowed for a "poppy red" color in these diagrams. I wasn't aware that poppies were red, but what do I know. These diagrams show the formation of a ferryl-to-ring charge-transfer complex, as part of a "charge-transfer state" or "charge-transfer electronic state," to allow for an electron transition to occur, and this transition is from one of the two roughly-degenerate, highest-occupied MOs (in this case--and as is usually the case in iron(IV)-hemes--these are the pi*xz and pi*yz antibonding MOs) to the lowest-unoccupied molecular orbital of the porphyrin ring that can be found in this particular electronic state (a state that I haven't defined here) of an iron(IV)-heme. In this case, it's one of the two eg(pi*) antibonding MOs (A and B, a.k.a. x and y) that tend to combine, through configuration interaction, into a new pair of MOs (one that is produced by constructive interaction and another that's produced through destructive overlap). The eg(A+B) and eg(A-B) configuration-interaction MOs actually appear to be quite similar, and the MO I drew might not actually be the true LUMO of the porphyrin moiety (it might be the eg(A-B)). It's noteworthy that the egA(pi*) and egB(pi*) MOs do not exhibit the same "appearance" in "Cartesian Coordinate System 1" as they do in "Cartesian Coordinate System 2," as I've named the two "systems" [see here: (http://hardcorephysiologyfun.blogspot.com/2010/05/occupancies-of-frontier-orbitals-of.html)]. I've redrawn the MOs from Fig. 9A, on p. 124, of the article by Hocking et al. (2007) [Hocking et al., 2007: (http://www.anorg.chem.uu.nl/PDF/hocking%20JACS2007.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17199290)], in coordinate system 1, instead of depicting them in the less-commonly-used coordinate system 2, with the x and y axes intersecting the nitrogen atoms of the pyrrole moieties of the porphyrin ring, that Hocking et al. (2007) show in Fig 9. The doming of the porphyrin ring normally occurs for very brief durations, such as less than one picosecond, during the catalytic cycles of heme-dependent enzymes. A "charge transfer" is basically just a one-electron transfer from a highest-occupied molecular orbital of one molecule or moiety of a molecule to a lowest-unoccupied molecular orbital of another molecule or of another moiety, within a single molecule. In this case, the ferryl moiety is undergoing a one-electron oxidation by the porphyrin ring.

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)].