In vivo kinetics of formate metabolism in folate-deficient and folate-replete rats [Molecular Bases of Disease]

December 5th, 2014 by Morrow, G. P., MacMillan, L., Lamarre, S. G., Young, S. K., MacFarlane, A. J., Brosnan, M. E., Brosnan, J. T.

It is now established that the mitochondrial production of formate is a major process in the endogenous generation of folate-linked one-carbon groups. We have developed an in vivo approach, involving the constant infusion of 13C-formate, until isotopic steady state is attained, to measure the rate of endogenous formate production in rats fed on either a folate-replete or folate-deficient diet. Formate was produced at a rate of 76 μmol·hr-1·100 g body weight-1 in the folate-replete rats and this was decreased by 44% in folate-deficient rats. This decreased formate production was confirmed in isolated rat liver mitochondria where formate production from serine, the principal precursor of one-carbon groups, was decreased by 85% although formate production from sarcosine and dimethylglycine (choline metabolites) was significantly increased. We attribute this unexpected result to the demonstrated production of formaldehyde by sarcosine dehydrogenase and dimethylglycine dehydrogenase from their respective substrates in the absence of tetrahydrofolate and subsequent formation of formate by formaldehyde dehydrogenase. Comparison of formate production with the ingestion of dietary formate precursors (serine, glycine, tryptophan, histidine, methionine and choline) showed that about 75% of these precursors were converted to formate, indicating that formate is a significant, though underappreciated, end-product of choline and amino acid oxidation. Ingestion of a high-protein diet did not result in increased production of formate, suggesting a regulation of the conversion of these precursors, at the mitochondrial level, to formate.