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Chapter: Introduction to Human Nutrition: The Vitamins

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Absorption and metabolism of folate

About 80% of dietary folate is as polyglutamates; a variable amount may be substituted with various one-carbon fragments or be present as dihydrofolate derivatives.

Absorption and metabolism of folate

About 80% of dietary folate is as polyglutamates; a variable amount may be substituted with various one-carbon fragments or be present as dihydrofolate derivatives. Folate conjugates are hydrolyzed in the small intestine by conjugase (pteroylpolyglutamate hydrolase), a zinc-dependent enzyme of the pancre-atic juice, bile, and mucosal brush border; zinc defi-ciency can impair folate absorption.

Free folate, released by conjugase action, is absorbed by active transport in the jejunum. The folate in milk is mainly bound to a specific binding protein; the protein–tetrahydrofolate complex is absorbed intact, mainly in the ileum, by a mechanism that is distinct from the active transport system for the absorption of free folate. The biological availability of folate from milk, or of folate from diets to which milk has been added, is considerably greater than that of unbound folate.

Much of the dietary folate undergoes methylation and reduction within the intestinal mucosa, so that what enters the portal bloodstream is largely 5-methyl-tetrahydrofolate. Other substituted and unsubstituted folate monoglutamates, and dihydrofo-late, are also absorbed; they are reduced and methyl-ated in the liver, then secreted in the bile. The liver also takes up various folates released by tissues; again, these are reduced, methylated and secreted in the bile.

 

The total daily enterohepatic circulation of folate is equivalent to about one-third of the dietary intake.

Despite this, there is very little fecal loss of folate; jejunal absorption of methyl-tetrahydrofolate is a very efficient process, and the fecal excretion of some 450 nmol (200 μg) of folates per day represents syn-thesis by intestinal flora and does not reflect intake to any significant extent.

Tissue uptake of folate

Methyl-tetrahydrofolate circulates bound to albumin, and is available for uptake by extrahepatic tissues, where it is trapped by formation of polyglutamates, which do not cross cell membranes.

The main circulating folate is methyl-tetrahydro-folate, which is a poor substrate for polyglutamylation; demethylation by the action of methionine synthetase  is required for effective metabolic trap-ping of folate. In vitamin B12 deficiency, when methio-nine synthetase activity is impaired, there will therefore be impairment of the uptake of folate into tissues.

Folate excretion

There is very little urinary loss of folate, only some 5–10 nmol/day. Not only is most folate in plasma bound to proteins (either folate binding protein for unsubstituted folate or albumin for methyl-tetrahydrofolate), and thus protected from glomeru-lar filtration, but the renal brush border has a high concentration of folate binding protein, which acts to reabsorb any filtered in the urine.

The catabolism of folate is largely by cleavage of the C-9–N-10 bond, catalyzed by carboxypeptidase G.

 

The p-aminobenzoic acid moiety is amidated and excreted in the urine as p-acetamidobenzoate and p-acetamidobenzoyl-glutamate; pterin is excreted either unchanged or as a variety of biologically inactive compounds.

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