Deficiency of either folate or cobalamin (vitamin B12) can lead to macrocytic anemia, with or without other cytopenias, caused by megaloblastic hematopoiesis that results from defective DNA synthesis. Folate in its tetrahydro form is a transporter of 1-carbon fragments, carried at any of three oxidation levels: methanol, formaldehyde, and formic acid. The oxidation levels of the folate-bound 1-carbon fragments can be altered by oxidation and reduction reactions that require nicotinamide adenine dinucleotide phosphate in its oxidized (NADP) or reduced (NADPH) forms, respectively. The original source of the folate-bound 1-carbon fragments is serine which, when it is converted to glycine, passes its terminal carbon to folate. The 1-carbon fragments thus generated are used for biosynthesis of purines, thymidine, and methionine. During biosynthesis of purines and methionine, free folate is released in its tetrahydro form. During biosynthesis of thymidine, tetrahydrofolate is oxidized to the dihydro form and must again be fully reduced by dihydrofolate reductase to continue functioning in 1-carbon metabolism. Methotrexate acts as an anticancer agent because it is an exceedingly powerful inhibitor of dihydrofolate reductase, thereby interdicting the regeneration of reduced folate.
In the cell, folates are serially conjugated to form a chain of 7 or 8 glutamic acid residues by the enzyme folylpolyglutamyl synthase (FPGS). These residues enable the retention of folates as polyglutamates in the cell. When natural food folates are absorbed from the intestine, a process that occurs chiefly in the duodenum and proximal jejunum, all but one of the glutamates are removed by the enzyme glutamate carboxypeptidase II (folate hydrolase). Resulting monoglutamate forms are then taken up by 1 of 2 folate-specific transporters located on the apical brush border, the reduced folate carrier (RFC), or the proton-coupled folate transporter (PCFT). Folates travel in the bloodstream and are taken up by the cells, mainly in the form of methyltetrahydrofolate monoglutamate. The newly absorbed folates are rapidly reglutamylated by FPGS in the cell. If glutamylation is impaired, the folates cannot be retained in the cell, resulting in an intracellular folate deficiency.
Cobalamin is required for two reactions: (1) intramitochondrial conversion of methylmalonyl coenzyme A (CoA), a product of catabolism of odd-carbon fatty acids as well as branched-chain amino acids and ketogenic amino acids, to succinyl CoA, a tricarboxylic acid (Krebs) cycle intermediate; and (2) cytosolic conversion of homocysteine to methionine, a reaction in which the methyl group of methyltetrahydrofolate is transferred to the sulfur atom of homocysteine. In cobalamin deficiency, methyltetrahydrofolate accumulates because, for practical purposes, donation of the methyl group to homocysteine is the only method of regenerating free tetrahydrofolate from methyltetrahydrofolate. Free tetrahydrofolate is an excellent substrate for FPGS; methyltetrahydrofolate is a poor substrate. Consequently, much of the methyltetrahydrofolate taken up by a cobalamin-deficient cell cannot be retained in the cell in the monoglutamated state. The megaloblastic anemia of cobalamin deficiency results from an intracellular folate deficiency that arises because of the cell’s limited ability to polyglutamylate methyltetrahydrofolate.
Absorption of cobalamin is a highly ...