Effects of Methylmalonic Acid on Serine and Glycine Metabolism and the Folate Cycle

In this article, Brothers et al. (1975) [Brothers et al., 1975: (http://www.ncbi.nlm.nih.gov/pubmed/1119804)] provide some evidence that the accumulation of intermediates in the propionate oxidation pathway in vitamin B12 (cobalamin) deficiency, resulting from decreases in methylmalonyl-CoA mutase activity, interfere with serine and glycine metabolism. Brothers et al. (1975) are essentially showing that the decrease in the activity of methylmalonyl-CoA mutase (MMM) that results from cobalamin depletion causes, via the effects of the accumulation of propionyl-CoA and methylmalonic acid, derived from methylmalonyl-CoA accumulation, a decrease in the activity of the glycine cleavage system (GCS). This is one of only a handful of articles that discusses relatively specific effects of low MMM activity, which occurs in cobalamin depletion, on folate-dependent enzymes.

Robertson et al. (1976) [Robertson et al., 1976: (http://www.ncbi.nlm.nih.gov/pubmed/1245786)] found, similarly, that the impairments in the oxidation of propionate in leukocytes of cobalamin-deficient people were correlated to the impairments in serine biosynthesis. Presumably this refers to cytosolic serine biosynthesis by cytosolic serine hydroxymethyltransferase (cSHMT) activity, but cobalamin depletion may also derange serine metabolism by other mechanisms (involving serine dehydratase, in other papers). That effect complicates the discussion in relation to MMM activity, and I'll collect some information on that at another time.

Hyndman et al. (2003) [Hyndman et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12601627)] also found evidence consistent with inhibition of the GCS by methylmalonic acid or other propionate-derived intermediates, and I talked about the way that mechanism might help explain the formate starvation hypothesis of cobalamin depletion (http://hardcorephysiologyfun.blogspot.com/2009/01/effects-of-cobalamin-on-serum-folate.html). But even in cells outside the liver, cells that lack the enzymes of the GCS, methylmalonic acid could just inhibit various enzymes of the TCA cycle and increase the intramitochondrial NADH/NAD+ ratio. One explanation for the "preferred direction," in the serine to glycine direction, of the activities of mitochondrial serine hydroxymethyltransferase (mtSHMT) and of the trifunctional DCS enzymes is that their activities, in that preferred direction, would appear to be dependent on, and presumably at least somewhat sensitive to changes in, a normal and high intramitochondrial NAD+/NADH ratio. Nakai et al. (1991) [Nakai et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1679919)] found that cobalamin depletion inhibited certain NAD+ dependent enzymes of the tricarboxylic acid (TCA) cycle and produced ATP depletion in the livers of rats, and Toyoshima et al. (1996) found, similarly, that cobalamin depletion inhibited the activities of TCA cycle enzymes (the TCA cycle is the Krebs cycle) in the livers of rats [Toyoshima et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8774237)]. Those effects of methylmalonic acid or related intermediates could inhibit mtSHMT activity in cells lacking the GCS enzymes and account for the results of Robertson et al. (1976). That effect could produce the formate-starvation effect, in cobalamin deficiency, of reducing mitochondrial formate export in cells lacking the GCS enzymes. I can't get the Robertson paper's full text at the moment, but it looks really interesting.