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CHAPTER 41 is prevented, the folates cannot be retained in the cell, resulting in an intracel-

FOLATE, COBALAMIN, AND lular folate deficiency.
Cobalamin is required for two reactions: intramitochondrial conversion of
MEGALOBLASTIC ANEMIAS methylmalonyl coenzyme A (CoA), a product of catabolism of branched-chain
amino acids, and ketogenic amino acids to succinyl CoA, a Krebs cycle inter-
mediate and cytosolic conversion of homocysteine to methionine, a reaction
in which the methyl group of methyltetrahydrofolate is donated to the sul-
Ralph Green fur 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
SUMMARY methyltetrahydrofolate. Free tetrahydrofolate is an excellent substrate for
FPGS; methyltetrahydrofolate is a poor substrate. Consequently, much of the
Deficiency of either folate or cobalamin (vitamin B ) leads to macrocytic ane- methyltetrahydrofolate taken up by a cobalamin-deficient cell leaks out of the
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mia with or without other cytopenias as a result of megaloblastic hematopoie- cell before it can be polyglutamylated. The megaloblastic anemia of cobalamin
sis, a manifestation of defective DNA synthesis. Folate in its tetrahydro form deficiency results from an intracellular folate deficiency that arises because of
is a transporter of one-carbon fragments, which it can carry at any of three the cell’s limited ability to polyglutamylate methyltetrahydrofolate.
oxidation levels: methanol, formaldehyde, or formic acid. The oxidation levels Absorption of cobalamin is a highly complex process. Upon arriving in
of the folate-bound one-carbon fragments can be altered by oxidation and the stomach, cobalamin is taken up by haptocorrin (HC) binder (also called R
reduction reactions that require nicotinamide adenine dinucleotide phosphate binder or cobalophilin), a glycoprotein found in virtually all secretions. When
in its oxidized (NADP) or reduced (NADPH) form. The primary source of the the cobalamin HC complex enters the duodenum, the HC is digested and
folate-bound one-carbon fragments is serine, which is converted to glycine the cobalamin is released into the intestinal lumen, where it is taken up by
as its terminal carbon is transferred to folate. The one-carbon fragments are intrinsic factor, a glycoprotein secreted by the gastric parietal cells. The cobal-
used for biosynthesis of purines, thymidine, and methionine. During biosyn- amin-intrinsic factor complex is absorbed by cells in the ileum through recep-
thesis of purines and methionine, free folate is released in its tetrahydro form. tor-mediated endocytosis, involving cubilin and other proteins. The cobalamin
During biosynthesis of thymidine, tetrahydrofolate is oxidized to the dihydro is released within lysosomes and transported to the blood where it circulates
form and must again be fully reduced by dihydrofolate reductase to continue bound to transcobalamin (TC), which delivers its cargo of cobalamin to cells
functioning in one-carbon metabolism. Methotrexate acts as an anticancer throughout the body. Folate (vitamin B ) and cobalamin (vitamin B ) play key
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agent because it is an exceedingly powerful inhibitor of dihydrofolate reduc- roles in the metabolic machinery of proliferating cells. 12
tase, thereby interdicting the generation of reduced folate. Megaloblastic anemia most commonly results from folate or cobalamin
In the cell, folates are conjugated by the addition of a chain of seven or (vitamin B ) deficiency. Folate deficiency often was nutritional in origin. It
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eight glutamic acid residues. These residues enable the retention of folates in may be seen in alcoholics, the elderly, the poor, but also is seen in patients
the cell. When folates are absorbed from the intestine, a process that occurs on hyperalimentation, with hemolytic anemia, or hemodialysis. In the many
chiefly in the duodenum and proximal jejunum, all but one of the glutamates countries that now practice folic acid fortification of the diet, such as the
is removed by the enzyme glutamate carboxypeptidase II (folate hydrolase). United States and Canada, the prevalence of folate deficiency has been dra-
Resulting monoglutamate forms are then taken up by one of two folate- matically reduced and nutritional folate deficiency has been virtually elimi-
specific transporters located on the apical brush border small bowel epithe- nated. In pregnancy, even a mild folate deficiency may be associated with
lium, the reduced folate carrier or the proton-coupled folate transporter. Blood defects in neural tube closure in the fetus, so pregnant women should always
folates are taken up by cells, mainly in the form of methyltetrahydrofolate receive folate supplements. The incidence of neural tube defects has fallen
monoglutamate. The newly absorbed folates are rapidly reglutamylated in considerably in North America since the introduction of folic acid fortification.
the cell by the enzyme folyl-polyglutamyl synthase (FPGS). If glutamylation Diagnosis of folate deficiency is based on measurements of folate in serum,
which furnishes information about the current level of folate, and in red cells,
which provide data on aggregate folate status over the preceding period dur-
ing which those red cells were produced. Nutritional folate deficiency is treated
with folic acid by mouth.
Acronyms and Abbreviations: AdoCbl, adenosylcobalamin; AICAR, 5-amino-4-
imidazole carboxamide ribotide; ATPase, adenosine triphosphatase; AZT, azidothy- Folate deficiency as a result of malabsorption occurs in tropical and non-
midine; CnCbl, cyanocobalamin; CoA, coenzyme A; CUB, cubilin; CUBAM, the binary tropical sprue. Folate deficiency as a result of tropical sprue is treated with
ileal cubilin receptor complex consisting of cubilin and amnionless; dTMP, deoxythy- folate supplements and antibiotics. In nontropical sprue, the treatment is
midine monophosphate; dU, deoxyuridine; dUMP, deoxyuridine monophosphate; folate plus a gluten-free diet.
FH , tetrahydrofolate; FPGS, folylpoly-γ-glutamyl synthase; [ H]Thd, [ H]thymidine; The most common cause of clinically apparent cobalamin deficiency is per-
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HC, haptocorrin; HCl, hydrochloric acid; IM, intramuscular; LDH, lactate dehydroge- nicious anemia (PA), a condition in which the portion of gastric mucosa that
nase; MCV, mean corpuscular volume; MeCbl, methylcobalamin; MRI, magnetic res- contains the parietal cells is destroyed through an autoimmune mechanism.
onance imaging; MTHFR, methylenetetrahydrofolate reductase; NADP, nicotinamide The parietal cells secrete intrinsic factor, which is essential for physiologic
adenine dinucleotide phosphate; NADPH, nicotinamide adenine dinucleotide phos- cobalamin absorption. Without intrinsic factor, a state of cobalamin deficiency
phate (reduced form); N O, nitrous oxide; OHCbl, hydroxocobalamin; PA, pernicious develops over the course of years. Cobalamin deficiency leads not only to meg-
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anemia; PteGlu, pteroylglutamic acid (folic acid); SAH, S-adenosylhomocysteine; aloblastic anemia but also to a demyelinating disease that manifests itself
SAMe, S-adenosylmethionine; TC, transcobalamin.

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