Plasma and urinary formate concentrations were recently found to be elevated during vitamin B12 and folate deficiencies. It was proposed that formate may be a valuable biomarker of impaired one-carbon metabolism. Formate is an essential intermediary metabolite in folate-mediated one-carbon metabolism and, despite its importance, our knowledge of its metabolism is limited. Formate can be produced from several substrates (e.g., methanol, branched chain fatty acids, amino acids), some reactions being folate-dependent while others are not. Formate removal proceeds via two pathways; the major one being folate-dependent. Formate is a potentially toxic molecule and we suggest that formate may play a role in some of the pathologies associated with defective one-carbon metabolism.Keywords: folic acid; formic acid; vitamin B2; vitamin B6; vitamin B12.
The importance of formate in intermediary metabolismFormic acid and its conjugate base formate are essential endogenous one-carbon metabolites in virtually all living organisms. Formic acid is sometimes called methanoic acid and with its chemical formula, HCOOH, it is the simplest carboxylic acid. The name formic acid takes its origin from formica , the latin for ants from which it was first distilled by Hulse and Fisher after they observed that the ants secreted a substance that caused blue flowers to turn red [ 1 ]. For some time this acid was believed by chemists to be acetic acid, malic acid or a mixture of both. However, after thorough examination, it was demonstrated that it differed from acetic and malic acids on the basis of its specific gravity, its reaction with alkali, its metallic salts and its chemical affinities [ 2 ]. Formic acid has a pKa of 3.77 and, as a result, most of it occurs in the body as the formate anion.The importance of formate in intermediary metabolism was recognized over six decades ago when it was shown that the carbon of formate is incorporated into nucleic acids and into the glucogenic amino acid serine [ 3 -6 ]. The incorporation of formate into nucleic acids and serine requires its activation by tetrahydrofolate (THF) [ 7 ] and therefore the metabolism of formate and folate are tightly related. Our current understanding of cellular folate metabolism involves two parallel pools of folate, one mitochondrial and the other cytosolic, connected by one-carbon donors such as glycine, serine and formate [ 8 ]. For instance, mitochondria can take up serine, oxidize two of its three carbons to formate and export this to the cytosol where it re-enters the folate pool to participate in methylation reactions or nucleotide synthesis (reviewed by Tibbetts [ 8 ]). These observations, combining the roles of formate in amino and nucleic acid metabolism, illustrate the central and essential role of formate in onecarbon metabolism.Despite the importance of formate in intermediary metabolism, our knowledge of its metabolism is limited. Annison [ 9 ] showed that formate represents 10% -30% of the total volatile fatty acids in the blood of numerous anim...