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Chapter 39 Megaloblastic Anemias 521

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5′-UTR Folate receptor with pregnancy complicated by neural tube defects is a striking
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human correlate of experimental studies in mice using antibodies.
mRNA Folate receptor-α also provides folate during neuronal regeneration
cis-element 77
and repair after injury where DNA methylation is also involved.
Stimulates No effect on interaction Folate Receptors and PCFT in Cerebral Folate
interaction Transport Across the Choroid Plexus

A new pathway of folate receptor-α dependent basolateral-to-apical
trans-factor transcytosis within vesicles across the choroid plexus cells followed
Homocysteine (hnRNP E1) Methionine by exosome-mediated folate delivery across the cerebrospinal fluid
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(CSF) into the brain parenchyma has been discovered. Briefly,
Methylcobalamin 5-methyl-THF is bound by glycosyl-phosphatidyl inositol (GPI)-
anchored folate receptor-α on the basolateral surface of choroid
Methionine synthase plexus cells. Following endocytosis there is sequential transfer of
folate receptor-α-bound folate from an early- to a later-endosomal
compartment called multivesicular bodies. The inward budding of
5-Methyl-tetrahydrofolate Tetrahydrofolate
(concentration dependent on one-carbon metabolism the limiting membrane of multivesicular bodies leads to formation of
A cellular delivery of folate) several intraluminal vesicles that now contain outward-facing folate
receptor-α. Following transcytosis of multivesicular bodies (contain-
ing their cargo of intraluminal vesicles) and eventual fusion with the
Cysteine S S Cysteine apical membrane, there is discharge of these intraluminal vesicles as
40 to 100 nm exosomes into the cerebrospinal fluid. These exosomes
mRNA (containing outward oriented folate receptor-α-bound folates) then
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binding site cross the ependymal cell layer and enter the brain parenchyma.
Some of the endocytosed folate receptor-α-bound folate is trans-
ported out of acidified endosomal compartments via proton-coupled
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folate transporters (PCFT) into the choroid plexus cell cytoplasm.
However, more information on the cooperative function of folate
receptor-α and PCFT in folate transport to the brain is required,
Homocysteine Homocysteine because loss of PCFT-mediated function in hereditary folate mal-
absorption profoundly compromises choroid plexus transport of
S S folates. 33,78
S S
Cysteine Cysteine Renal Retention of Folates (and Cobalamin)

mRNA After glomerular filtration, luminal folate binds folate receptor-α in
binding site the brush border membranes of proximal renal tubular cells and is
B internalized rapidly by folate receptor-α–mediated endocytosis; in
the low pH of endocytotic vesicles, there is dissociation of folates
Fig. 39.6 MODEL FOR HOW THE CELL SENSES FOLATE DEFI- and slow transport across basolateral membranes into the blood,
CIENCY AND RESPONDS BY UPREGULATING FOLATE RECEP- with recycling of apo-folate receptor-α back to the luminal brush
TORS. Note how this model links perturbed folate metabolism, ribonucleic border membrane. 41,42,48 A large 550-kDa membrane protein called
acid (RNA)–protein interaction, and coordinated translational regulation of megalin, which interacts with cubilin and is found in renal proximal
folate receptor to optimize cellular folate uptake and restore folate homeosta- epithelial cells, functions as a multiligand receptor for a variety of
sis. The prominent red arrow highlights the critical role of heterogeneous macromolecules. 79,80 Megalin also specifically binds to and medi-
nuclear ribonucleoprotein E1 (hnRNP-E1) as a candidate sensor of cellular ates endocytosis of TCII-cobalamin complexes as well as filtered
folate deficiency. (A) Reduced folate availability results in inactivation of folate bound to soluble folate-binding proteins in kidney proximal
methionine synthase and intracellular homocysteine buildup, which induces tubules. 81
a direct posttranslational homocysteinylation of hnRNP-E1 via targeted
homocysteine-S-S-cysteine mixed disulfide bonds; this results in the unmask-
ing of a high-affinity folate receptor messenger RNA (mRNA) cis-element INTRACELLULAR ONE-CARBON METABOLISM AND
binding site and leads to increased translation of folate receptor-α. The net COBALAMIN–FOLATE RELATIONSHIPS
effect is a homeostatic response that aims to restore intracellular folate con-
centrations to normal by upregulating cell surface folate receptor. Folate Cellular Folate Retention and One-Carbon Metabolism
repletion reactivates methionine synthase, which converts homocysteine to
methionine. Methionine has no effect on the RNA-protein interaction that Polyglutamylation of folate by the enzyme folylpolyglutamate syn-
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leads to reduced folate receptor-α synthesis and its downregulation. (Note: thase catalyzes the addition of multiple glutamate equivalents to
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other metabolic pathways involving homocysteine are not included.) (B) A their γ-carboxyl residue (see Figs. 39.4 and 39.5). In most eukaryotic
proposed mechanism for the unmasking of a cryptic mRNA binding site in cells, the pentaglutamate and hexaglutamate forms predominate.
hnRNP-E1 following the covalent binding of L-homocysteine, through the Polyglutamylation is needed to retain folates (and antifolates) within
replacement of one (of many potential) cysteine disulfide bonds by protein- cells; in addition, polyglutamylated folates are more efficient sub-
cysteine-S-S-homocysteine mixed disulfide bonds. 5′-UTR, 5′ Untranslated strates for folate-dependent enzymes. In human erythrocytes (red
region. (From Tang YS, Khan RA, Zhang Y, et al: Incrimination of heterogeneous blood cells [RBCs]), folate is accumulated at earlier stages within
nuclear ribonucleoprotein E1 (hnRNP-E1) as a candidate sensor of physiological folate the marrow by folate receptors 82,83 ; on maturation, more than 90%
deficiency. J Biol Chem 286:39100, 2011.) of H 4PteGlu (n) molecules interact with hemoglobin, which, because
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of its high capacity, assists in intracellular folate retention. Folate
turnover and catabolism in the cytoplasm can be experimentally