C5 Ketones (3-hydroxypentanoate/3-hydroxyvalerate and 3-ketopentanoate/3-ketovalerate) as Anaplerotic Precursors of Succinyl-CoA (from Propionyl-CoA)

This article [Roe et al., 2002: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=151060&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/12122118)] is one of many articles showing that odd-chain fatty acids, such as the C7 (7-carbon) fatty acid heptanoate (derived from triheptanoin, which is triheptanoylglycerol, in this article), are metabolized into both propionyl-CoA (a C3 fatty acyl-CoA) and acetyl-CoA (a C2 acyl-CoA) and are generally much more effective in the treatment of genetic disorders of beta-oxidation than even-numbered fatty acids are (such as octanoate and decanoate, the prototypical "medium-chain triglycerides," or MCTs). Triheptanoin is a precursor of the C5 ketones 3-hydroxypentanoate (a.k.a. beta-hydroxypentanoate or beta-hydroxyvalerate or 3-hydroxyvalerate) and 3-ketopentanoate (a.k.a. 3-ketovalerate or beta-ketovalerate or beta-ketopentanoate), and these can be oxidized much more readily, by neurons and astrocytes in the brain and also by cells in other extrahepatic tissues, than heptanoate can.

The C5 ketones are advantageous in these contexts because the oxidation of 3-hydroxybutyrate or acetoacetate, the classical ketones, yields only acetyl-CoA and leads to an "overload" of acetyl-CoA in the TCA cycle. I've discussed the reasons this becomes problematic in past postings. In some cases, the administration of citrate or other TCA cycle intermediates other than acetyl-CoA (anaplerotic compounds) has been as useful, in conjunction with C2 precursors (i.e. MCTs), as the use of triheptanoin has been. It's conceivable that in epilepsy, for example, the acetyl-CoA overload is actually therapeutic, up to a point. That's more or less at the root of the arguments that Yudkoff and colleagues have made in their articles, in my opinion. They say that the inhibition of the overall activity of the pyruvate dehydrogenase complex by an excess of acetyl-CoA is one factor (one of several factors) that causes the equilibrium of the mitochondrial glutamate-oxaloacetate transaminase reaction to be shifted toward glutamate formation (and to thereby increase the glutamate/aspartate ratio, both intramitochondrially and extramitochondrially and lead to an increase in GABA formation from the extra glutamate, etc.). But in conditions other than epilepsy, this is less likely to be the case (the excess of acetyl-CoA, derived from the oxidation of C4 ketones, like 3-hydroxybutyrate, is less likely to be beneficial, past a certain point), and researchers should be considering the administration of soluble salts of C5 ketones as an approach to the treatments of some of these supposedly "ketone-responsive" conditions (the potentially therapeutic effects of C4 ketones have been researched and discussed, at length, in the context of many neurodegenerative and psychiatric conditions, etc.).

If it weren't for the fact that massive amounts of glycine are provided along with propionyl-L-carnitine (PLC) in some preparations, I might be inclined say that propionylcarnitine would be a good anaplerotic compound and substitute for triheptanoin. Unfortunately, in my opinion, the glycine provided along with PLC, in some preparations, compromises its usefulness. There are still a lot of problems with the planning that goes into the choices of salts of compounds and in the development of pharmaceutical dosage forms in general. Manufacturers cavalierly choose calcium salts of compounds, for example, and don't consider that high doses of calcium can foster thrombogenicity, in my opinion [as discussed in past postings (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/pyridoxine-calcium-channels-and.html)]. Glycine is an excitatory neurotransmitter in the brain, although most researchers and people seem to still think it's only inhibitory (it's inhibitory in the spinal cord, at the strychnine-sensitive glycine binding sites on NMDA receptors, but it's predominantly excitatory in the brainstem). There's some recent research on mice with loss of function mutations in glycine transporters that illustrates the way glycine behaves in the brain (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22glycine+transporter%22+mouse+deletion), and I think free form glycine should not be used in any nutritional supplements. These are just my opinions, of course.