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Deficiency of either folate or cobalamin (vitamin B12) leads to macrocytic anemia with or without other cytopenias as a result of megaloblastic hematopoiesis, a manifestation of defective DNA synthesis. Folate in its tetrahydro form is a transporter of one-carbon fragments, which it can carry at any of three oxidation levels: methanol, formaldehyde, or formic acid. The oxidation levels of the folate-bound one-carbon fragments can be altered by oxidation and reduction reactions that require nicotinamide adenine dinucleotide phosphate in its oxidized (NADP) or reduced (NADPH) form. The primary source of the folate-bound one-carbon fragments is serine, which is converted to glycine as its terminal carbon is transferred to folate. The one-carbon fragments 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 one-carbon metabolism. Methotrexate acts as an anticancer agent because it is an exceedingly powerful inhibitor of dihydrofolate reductase, thereby interdicting the generation of reduced folate.

In the cell, folates are conjugated by the addition of a chain of seven or eight glutamic acid residues. These residues enable the retention of folates in the cell. When folates are absorbed from the intestine, a process that occurs chiefly in the duodenum and proximal jejunum, all but one of the glutamates is removed by the enzyme glutamate carboxypeptidase II (folate hydrolase). Resulting monoglutamate forms are then taken up by one of two folate-specific transporters located on the apical brush border small bowel epithelium, the reduced folate carrier or the proton-coupled folate transporter. Blood folates are taken up by cells, mainly in the form of methyltetrahydrofolate monoglutamate. The newly absorbed folates are rapidly reglutamylated in the cell by the enzyme folyl-polyglutamyl synthase (FPGS). If glutamylation is prevented, the folates cannot be retained in the cell, resulting in an intracellular folate deficiency.

Cobalamin is required for two reactions: intramitochondrial conversion of methylmalonyl coenzyme A (CoA), a product of catabolism of branched-chain amino acids, and ketogenic amino acids to succinyl CoA, a Krebs cycle intermediate and cytosolic conversion of homocysteine to methionine, a reaction in which the methyl group of methyltetrahydrofolate is donated 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 generating 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 leaks out of the cell before it can be polyglutamylated. 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 complex process. Upon arriving in the stomach, cobalamin is taken up by haptocorrin (HC) binder (also called R binder...

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