TY - CHAP M1 - Book, Section TI - Folate, Cobalamin, and Megaloblastic Anemias A1 - Green, Ralph A1 - Mitra, Anaya Datta A2 - Kaushansky, Kenneth A2 - Prchal, Josef T. A2 - Burns, Linda J. A2 - Lichtman, Marshall A. A2 - Levi, Marcel A2 - Linch, David C. PY - 2021 T2 - Williams Hematology, 10e AB - SUMMARYDeficiency of either folate or cobalamin (vitamin B12) leads 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, which it can carry at any of 3 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 primary source of the folate-bound 1-carbon fragments is serine, which is converted to glycine as it passes its terminal carbon to folate. The 1-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 1-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 7 or 8 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 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 in the cell by the enzyme folylpolyglutamyl synthase. 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 tricarboxylic acid (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 folylpolyglutamyl synthase; 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 or cobalophilin), a glycoprotein found in virtually all secretions. When the ... SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/28 UR - hemonc.mhmedical.com/content.aspx?aid=1178740357 ER -