Coenzyme A Sequestration

This is a great article that helps me, to some extent, understand anaplerosis and the acetyl-CoA- and acetoacetyl-CoA-mediated sequestration of free coenzyme A:

http://ajpheart.physiology.org/cgi/content/abstract/268/1/H441 (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/7840294?dopt=Abstract) (Russell et al., 1995)

It's interesting that Russell et al. (1995) found that propionate + carnitine did not mimic the anaplerotic effect of propionylcarnitine. The authors are saying that the alpha-ketoglutarate dehydrogenase (KGDH) enzyme complex (a.k.a. 2-oxoglutarate dehydrogenase) is a key step in the TCA cycle that is inhibited by a decrease in free CoA availability that results from CoA sequestration as acetyl-CoA and acetoacetyl-CoA. This occurs especially when the cardiac myocytes are oxidizing ketones, such as in the fasted state. It's because free CoA is a substrate for KGDH, which catalyzes the NAD+ dependent conversion of CoA and 2-oxoglutarate into CO2 and succinyl-CoA . Even though providing more succinyl-CoA could be expected to exert feedback inhibition of KGDH activity, I guess the KGDH activity is already inhibited by the absence of CoA (meaning that the succinyl-CoA pool is already low).

Russell et al. (1995) also found that propionylcarnitine nonsignificantly elevated the free CoA pool. I'll have to read more about this. It's relevant to the neuroprotective effects of vitamin B12 and possibly uridine also, given that uracil is metabolized into acetyl-CoA (and I think thymine, the pyrimidine base of thymidine, is degraded into propionyl-CoA).

The type of thing that would concern me about the use of something like propionyl-L-carnitine, such as in peripheral vascular disease or as a neuroprotective, would be that the short-chain acyl-CoA's would reduce the levels of free CoA. CoA sequestration is thought to be a mechanism by which aspirin, such as in Reye's syndrome, and valproic acid can cause liver toxicity. There are valproyl-CoA esters formed that sequester CoA, and ibuprofen (a propionic acid derivative) can also cause coenzyme A sequestration (albeit to a lesser extent than aspirin) [Tracy et al., 1993: (http://dmd.aspetjournals.org/cgi/content/abstract/21/1/114) (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/8095203?dopt=Abstract)]. Here's an example of an article that discusses some of that:

http://www.ncbi.nlm.nih.gov/pubmed/9204409 (Fromenty and Pessayre, 1997)

The explanation for the prohibition of aspirin use during something like influenza, in children and anyone who is younger than 18, is that the liver and other cells rely more heavily on beta-oxidation for ATP production in that age range. Something like influenza inhibits mitochondrial functioning in general (via the effects of TNF-alpha or by reactive oxygen and nitrogen species from neutrophils, etc.), and then the aspirin inhibits beta-oxidation and can produce fatty liver disease or lipid accumulation in the endothelial cells of the cerebral blood vessels (Reye's syndrome). It's a mitochondrial injury, and researchers have proposed the same types of mechanisms (oxidative stress in the face of some specific inhibitory effect on mitochondrial functioning, which would tend to itself produce oxidative stress) to account for drug-induced or other-cause-induced fatty liver disease (which is basically mitochondrial damage in the liver).

I think the issue is that bypassing the carnitine-mediated transport system into the mitochondria, by increasing propionylcarnitine or propionyl-CoA derived from something like heptanoic acid acid, could be a double-edged sword. The carnitine-independent (or "-less dependent") transport allows rapid oxidation of odd-chain fatty acids, but it seems like there would still be some of the same potential for CoA sequestration, or some other effect, and toxicity that occurs with octanoic acid/trioctanoin.