The Propionate Pathway and Methylmalonyl-CoA Mutase

This is a great article on so-called anaplerotic substrates, and the discussion about odd-chain fatty acid metabolism is really interesting. Heptanoic acid (in triglyceride form, triheptanoin) is an odd-chain fatty acid that can be oxidized into propionyl-CoA and then succinyl-CoA by the AdoCbl (5'-deoxyadenosylcobalamin) dependent methylmalonyl-CoA mutase enzyme. It's supposed to work better than octanoic acid, which can cause fatty liver and act as a sort of detergent that disrupts the mitochondrial membranes or something. I forget the details.

I don't know, though, about this supposed advantage of odd-chain fatty acids. This discussion about propionate bypassing carnitine palmitoyltransferase sounds like the things people used to say about octanoic acid, that it was oxidized like carbohydrates. It didn't end up working that way, really, and its oxidation wasn't completely independent of carnitine palmitoyltransferase. It's still a good article and is very relevant to the neuroprotective effects of B12 deficiency/depletion. The thing they say about acetyl-CoA "overload," sort of, causing heart problems is something I've heard about before. It's really interesting, and supposedly an increase in the ratio of acetylcarnitine to other acylcarnitines or to free carnitine or something can produce that effect:

http://www.ncbi.nlm.nih.gov/pubmed/16763895 (Brunengraber et al., 2006)

This article about the inhibition of the malate-aspartate shuttle, per se, causing inhibition of the TCA cycle also has some good references about the disadvantages of octanoic acid:

http://www.ncbi.nlm.nih.gov/pubmed/9737943 (Barron et al., 1998)

This article refers to some of the cardiology-related applications of the propionate pathway, and they were using propionyl-L-carnitine in some multicenter trials for Raynaud's syndrome or something similar. I wonder how much propionate is actually derived from propionylcarnitine, though:

http://www.jbc.org/cgi/content/full/278/37/34959 (Anita Reszko et al., 2003)

This article shows that propionyl-CoA and methylmalonyl-CoA accumulate in large amounts (undesirably) in the livers of B12-deficient rats (because of inhibition of methylmalonyl-CoA mutase):

http://jn.nutrition.org/cgi/reprint/120/3/290 (Eric Brass et al., 1990)

Propionyl-CoA accumulation is really bad, even though methylmalonic acid/methylcitric acid accumulation has been more heavily studied in relation to B12 deficiency.