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Folate in its tetrahydro form is a transporter of one-carbon fragments, which it can carry at any of three oxidation levels: methanol, formaldehyde, and 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 and nicotinamide adenine dinucleotide phosphate (reduced form, NADPH), respectively. The chief source of the folate-bound one-carbon fragments is serine, which is converted to glycine as it passes its terminal carbon 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 be re-reduced by dihydrofolate reductase in order to continue functioning in one-carbon metabolism. Methotrexate acts as an anticancer agent because it is an exceedingly powerful inhibitor of dihydrofolate reductase.

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 are removed by the enzyme conjugase. Folates travel in the bloodstream and are taken up by the cells, mainly in the form of unconjugated methyltetrahydrofolate. The newly absorbed folates are rapidly reconjugated in the cell. If reconjugation 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 the conjugase; 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 conjugated. The megaloblastic anemia of cobalamin deficiency results from an intracellular folate deficiency that arises because of the cell’s limited ability to conjugate 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 or cobalophilin), a glycoprotein found in virtually all secretions. When the cobalamin HC complex enters the duodenum, the HC is digested and the cobalamin is released into the intestinal lumen, where it is taken up by intrinsic factor, a glycoprotein secreted by the gastric parietal cells. The cobalamin-intrinsic factor complex is absorbed by cells in the ileum through receptor-mediated endocytosis, involving cubilin and other proteins. The cobalamin ...

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