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588 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 589

METABOLISM protein in granulocytes has been localized to the specific granules, from
Tritiated folylmonoglutamate ( H-F) administered intravenously is which it is released when the granulocytes are stimulated.
3
almost completely removed from the bloodstream in a few minutes.
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Uptake involves two classes of folate-binding proteins : high-affin- EXCRETION
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ity folate receptors that concentrate folate in intracellular vesicles and Folates are both resorbed and secreted by the kidney. Resorption is
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a membrane folate transporter that transports folate from the vesicles accomplished by a membrane-bound high-affinity folate receptor (K
m
into the cytosol. The high-affinity receptors, which are attached to the for N -methyltetrahydrofolate = 0.4 nM) located in the brush-borders
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outer surface of the cell membrane by glycosyl-phosphatidylinositol of the proximal tubules. Filtered folate may thus be returned to the
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linkages and lack an intracytoplasmic portion, bind very tightly (K bloodstream. There is resorption of most, but not all, of the filtered
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d
[distribution coefficient] in the nanomolar range) to most physiologic folate.
folate monoglutamates, particularly N -methyltetrahydrofolate, the In humans, intact folates and their cleavage products are excreted
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major circulating folate. The folate receptors exist in various isoforms by the kidney at a rate of 2 to 5 mcg/day. A small percentage of paren-
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(of which α and β are the most important). Folate receptor-α, despite terally administered labeled folate is recoverable in the feces and mainly
its missing cytoplasmic extension, is effective in mediating endocyto- represents unreabsorbed folate from the enterohepatic cycle. 63
sis. Their very high affinity enables the receptors to take up N -meth-
5
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yltetrahydrofolate from the plasma, even at its ambient concentration of
approximately 10 nM. The membrane folate transporter is a probenecid- ASSAY OF SERUM FOLATE
inhibitable organic anion carrier that, among other functions, car- Folates are measured by chemiluminescent methods using various
ries reduced folates and methotrexate in and out of the cytoplasm. Its folate binders. These assays are identical in principle to the radioligand
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K for folate is in the micromolar range. Once internalized, the folates binding assays that they have replaced.
m
are retained by the cells partly through polyglutamylation as well as
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through tight association with a set of intracellular folate-binding pro- COBALAMIN
teins. Three of these proteins are enzymes involved in methyl group
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metabolism: sarcosine dehydrogenase and dimethylglycine dehydroge- CHEMISTRY
nase (mitochondrial) and glycine N-methyl transferase (cytosolic).
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Why these enzymes bind folate so avidly or whether this binding Structure and Nomenclature
affects overall methyl group metabolism is unknown, although glycine The cobalamin molecule has two major portions: a porphyrin-like
N-methyl transferase is speculated to regulate methyl group metabo- near-planar macrocycle known as corrin, and a nucleotide that lies
lism by controlling the tissue concentration of S-adenosylhomocysteine almost perpendicular to the corrin ring (Fig. 41–6). The corrin moi-
(SAH), one of its reaction products and a potent inhibitor of most ety contains four reduced pyrrole rings that bind a central cobalt
methyltransferases. atom whose two remaining coordination positions are occupied by a
Folates have been found in all body tissues that have been ana- 5,6-dimethylbenzimidazolyl (5,6-DMB) group, below the ring and vari-
lyzed. The principal form of the vitamin in tissues and in blood appears ous ligands (in this case, —N in the form of CN) above the ring. 64
to be the N -methyl form. The total folate pool turns over very slowly. Compounds containing the corrin ring are known as corrinoids.
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50
5
Degradation accounts for a portion of this turnover. p-Aminoben- The cobalamins are corrinoids whose nucleotide contains 5,6-DMB.
zoylglutamate has been identified as a breakdown product. The fate of Two connections exist between the corrin and the nucleotide: (1) a
the pteridine moiety is unknown. bond between the nucleotide phosphate and a side chain in ring D, and
(2) a bond between cobalt and a nitrogen atom of benzimidazole. Figure
FOLATE-BINDING PROTEINS OF SERUM AND 41–7 summarizes the numbering and ring designations of the corrin
system.
MILK The term vitamin B is sometimes used as a generic term for the
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The soluble folate-binding proteins of serum and milk are high-affinity cobalamins. The term probably is best reserved, however, as an alterna-
folate receptors that are released from cell membranes by proteolysis. tive name for cyanocobalamin, the usual therapeutic form of cobalamin.
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These proteins can be detected in approximately 15 percent of nor-
mal individuals and are found at increased levels in some pregnant
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women, women taking oral contraceptives, folate-deficient alcoholics
(but not patients with cobalamin deficiency), and patients with ure-
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mia, hepatic cirrhosis, and chronic myelogenous leukemia. In normal
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subjects, the proteins are approximately two-thirds saturated and have
a total folate-binding capacity of approximately 175 pg/mL of serum.
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The proteins may not be detected in some subjects because of complete
saturation of the proteins with endogenous unlabeled folate. Serum
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folate-binding protein has an Mr of 40,000 and prefers oxidized to
reduced folates. 55 Nitrogen
Folate-binding proteins have been found in milk and in normal Carbon
Oxygen
granulocytes. Folate bound to the milk folate binder in suckling ani- Phosphorus
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mals is absorbed chiefly in the ileum rather than the jejunum, the Cobalt
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principal site of absorption of free folate. The milk folate binder, a gly-
coprotein, also promotes folate transport into the liver via the asialo- A B
glycoprotein receptor. The milk folate binder is speculated to protect Figure 41–6. A. Structure of cyanocobalamin (CnCbl; vitamin B ). B.
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an infant’s folate supply by preventing bacteria from sequestering the Partial structure of CnCbl showing the relationship between the corrin
vitamin away from the intestinal absorptive surface. The folate-binding ring and the nucleotide.
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