Tissue Uptake and Metabolism of Folate

Methyl-tetrahydrofolate from the intestinal mucosa circulates bound to albumin and is the main vitamer for uptake by extrahepatic tissues. Small amounts of other one-carbon substituted folates also circulate (about 10% to 15% of plasma folate is 10-formyl-tetrahydrofolate) and are also available for tissue uptake. There are two mechanisms for tissue uptake of folate:

1. The reduced folate transporter is a transmembrane protein with a high affinity for methyl-tetrahydrofolate and a low affinity for other vitamers. It is especially active in enterocytes and renal tubule epithelium, but is also found in other cells (Sirotnak and Tolner, 1999).

2. The folate receptor is a glycophosphatidyl inositol anchored cell surface protein with a broader specificity that permits uptake of folate by receptor-mediated endocytosis. At times of low folate requirement, the receptor is in intracellular vesicles, which migrate to the cell surface when the requirement for folate increases (Doucette and Stevens, 2001).

Demethylated tetrahydrofolate monoglutamate is released by extrahepatic tissues and is transported bound to a plasma folate binding protein similar to that in milk. It has a very low affinity for methyl-tetrahydrofolate and other one-carbon substituted derivatives. It functions mainly to return folate to the liver, where it is either conjugated for storage or methylated to 5-methyl-tetrahydrofolate that is secreted in the bile.

Red blood cells contain a several-hundred-fold higher concentration of folate than does plasma, incorporated during erythropoeisis rather than taken upfrom the circulation, as polyglutamates bound to hemoglobin. Folate binds to deoxyhemoglobin in competition with 2,3-bisphophoglycerate, but does not bind significantly to oxyhemoglobin. The binding affinity is low, but because of the high concentration of hemoglobin in erythrocytes, essentially all of the folate in cells from venous blood will be bound. The function of hemoglobin binding is not known, and it may not serve any physiological purpose, although, as discussed in Section 10.10.1, it may result in falsely low values for erythrocyte folate as an index of folate status.

10.2.2.1 Poly-y-glutamylation of Folate Folate monoglutamates cross cell membranes readily, whereas polyglutamates do not; therefore, formation of conjugates permits intracellular accumulation of folate. Rapid formation of at least a diglutamate is essential for tissue retention of folate. Further elongation of the polyglutamate chain to form the metabolically active coenzymes can proceed in a more leisurely fashion.

A single enzyme, folate polyglutamate synthetase, catalyzes the formation of all the polyglutamates. At high concentrations of substrate, the diglutamate is the main or sole product; increasing amounts of tri-, tetra-, penta-, and hexaglutamates are formed as the concentration of tetrahydrofolate monoglutamate decreases. This is because, unlike other folate utilizing enzymes, the Km of folate polyglutamate synthetase increases as the length of the polyglutamate chain increases, and short-chain polyglutamates are the preferred substrates. The rate of reaction with long-chain polyglutamates is considerably lower than with short-chain substrates.

Folate polyglutamate synthetase binds ATP, tetrahydrofolate-(oligo)-glutamate, then glutamate sequentially forming an intermediate folate polyglutamate phosphate. The immediate product is released to compete for enzyme binding with other intracellular folate conjugates, rather than undergoing sequential glutamyl transfer while remaining enzyme bound (Cichowicz and Shane, 1987).

The principal substrate for glutamylation is free tetrahydrofolate; one-carbon substituted folates are poor substrates. Because the main circulating folate, and the main form that is taken upinto tissues, is methyl-tetrahydrofolate, demethylation by the action of methionine synthetase (Section 10.3.3) is essential for effective metabolic trapping of folate. In vitamin B12 deficiency, when methionine synthetase activity is impaired, there will be impairment of the retention of folate in tissues.

Under normal conditions, the predominant folates in liver are pentaglu-tamates, with small amounts of tetra- and hexaglutamates. The extent of poly-glutamylation is controlled to a great extent by the availability of folate; in deficient animals, hexa- to octaglutamates predominate, whereas in supplemented animals, liver folate is mainly as the tri- to pentaglutamates (Cassady etal., 1980).

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