Transcript Folat

Folate
Folate
• Folic acid is the term used to refer to the oxidized form
of the vitamin found in fortified foods and in
supplements.
• Folate refers to the reduced form of the vitamin found
naturally in foods and in biological tissues.
• The Latin word folium means “leaf,” and the word
folate from Italian means “foliage.”
• Folate’s and vitamin B12’s discovery resulted from the
search to cure the disorder megablastic anemia, a
problem in the late 1870s and early 1880s.
• As with many of the other vitamins, eating liver was
shown to cure the condition.
Folate structure
• Folate is made up of three distinct parts, all must
be present for vitamin activity.
• Called pteridine or pterin
• P-aminobenzoic acid (PABA).
• L-glutamic acid to form folate
• Although humans can synthesize all the
component parts of the vitamin, they do not have
the enzyme necessary for the coupling of the
pterin molecule to PABA to form pteroic acid.
Folic Acid - Folate
(Petroyl-monoglutamic acid)
Sources
• Good food sources of folate include mushrooms and green
vegetables such as spinach, brussels sprouts, broccoli,
asparagus, and turnip greens, okra, among others, as well
as peanuts, legumes (especially lima, pinto, and kidney
beans), lentils, fruits (especially strawberries and oranges)
and their juices, and liver.
• Raw foods typically are higher in folate than cooked foods
because of folate losses incurred with cooking. Fortification
of flours, grains, and cereals with folic acid (140 μg folic
acid per 100 g of product) wasinitiated in 1998. Thus,
fortified cereals, breads, and grain products now represent
major sources of the vitamin.
• Some juices also are now fortified with folic acid.
Sources
Sources
• Folate bioavailability from foods varies, from about
10% to 98%, because of a variety of factors.
• Variations in intestinal conditions such as pH, genetic
variations in enzymatic activity needed for folate
digestion, dietary constituents such as inhibitors, and
the food matrix, for example, influence bioavailability.
• Reduced forms of folate pteroylpolyglutamates in
foods are labile and easily oxidized.
• The folate in milk is bound to a high-affinity folatebinding-protein, which appears to enhance its
bioavailability.
DIGESTION, ABSORPTION, TRANSPORT,
AND STORAGE
• Before the polyglutamate forms of folate in foods can be absorbed,
they must be hydrolyzed to the monoglutamate form. This
hydrolysis or deconjugation is performed by at least two hydrolases
or conjugases.
• The conjugases found in human jejunal mucosa, pancreatic juice
and bile.
• The conjugases are:
• Brush border conjugase is zinc-dependent.
• Zinc deficiency can diminish folate absorption.
• Chronic alcohol ingestion can diminish absorbtion.
• Conjugase inhibitors in foods such as legumes, lentils, cabbage, and
oranges also diminish conjugase activity to impair digestion.
• pH sensitive.
Absorption
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Transport system by several carriers:
carriers mediated in the proximal small intestine low concentration.
Saturable, energy, and sodium. Affected by pH (5.5-6) and glucose.
folate protein carrier
Carrier mediated for reduced folate white blood cells and other tissues
transports 5-methyl THF
Simple diffusion pharmacological doses of the vitamin are consumed.
Absorption is most efficient in the jejunum.
Inside the intestinal cell:
Folate reduced to THF
Occurs via NADPH-dependent dihydrofolate reductase.
Four additional hydrogens added at positions 5, 6, 7, and 8.
THF methylated to 5-methyl THF or formylated.
Transport and Storage
• Free in plasma: monoglyutamate derivatives, mainly THF.
• Uptake by the liver using carrier and converted to 5-methyl THF and 10formyl-THF (tightly formulated).
• 33% as THF, 37% as 5-methyl THF, 23% as 10-formyl THF and 7% as 5formyl THF.
• Most of 5-methyl THF and 10-formyl THF is excreted into the bile.
• glutamates typically varying in length from 3 to 9. Folylpolyglutamate
• The liver stores about one-half of the body’s folate. And polyglutamate
form.
• Liver / tissue
• Demethylation
• Elongation of glutamate tail, this addition
• Pteroyloplyglutamate syntheses (PPS)
• Traps folate inside cell
• Allows production of other forms
Transport and storage
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Blood:
Folate is found as monoglutamate
Primarily N5-mythyle-NHF
2/3 bound to protein albumin, 1/3 free
RBC- folate level is index of longer-term (23mo) folate status than dose plasma.
Tissue distribution
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Total body content:
5-10mg (50% in liver)
In tissues with:
Rapid cell division: low 5-methyl-THF and high 10
formyl-THF
• Low cell division: 5-methyl-THF dominates
• Folate mainly in mitochondriah (10-formyl-THF)
and cytosol (5-methyl-THF)
• Stored as polyglutamates
FUNCTIONS AND MECHANISMS OF ACTION
• THF functions in the body as a coenzyme in both
the mitochondria and cytoplasm to accept onecarbon groups typically generated from amino
acid metabolism.
• These THF derivatives then serve as donors of
one-carbon units in a variety of synthetic
reactions, such as dispensable amino acid
synthesis.
• Methyl group accepted by THF is bonded to its
nitrogen in position 5 or 10 or to both.
FUNCTIONS AND MECHANISMS OF ACTION
• Genetic polymorphisms in some of the folate-dependent
enzymes have been identified.
• Several mutations in methylene THF reductase (MTHFR)
have been demonstrated converts 5,10-methylene THF to
5-methyl THF.
• Its requires riboflavin as FAD as a prosthetic group.
• Mutations in MTHFR impair 5-methyl THF formation and
thus reduce remethylation of homocysteine, resulting in
hyperhomocysteinemia, a risk factor for heart disease.
FUNCTIONS AND MECHANISMS OF ACTION
• The THF derivatives, which participate in a
variety of reactions, are illustrated as follows:
Function and mechanism of action
Amino acid metabolism
• Histidine Histidine metabolism requires THF.
• Histidine undergo to determination and further
metabolism to yield formiminoglutamate (FIGLU).
• This reaction can be used as a basis for determining folate
deficiency.
• With folate deficiency, FIGLU accumulates in the blood and
excreted in higher concentration in the urine.
METABOLISM AND EXCRETION
• Folate is excreted from the body in both the urine and the
feces.
• Within the kidney, folate-binding proteins present in the
renal brush border and coupled with tubular reabsorption
of folate help the body retain needed folate.
• Excess folate is excreted in the urine with some folate
excreted intact and some catabolized in the liver prior to
excretion.
• In addition to urinary losses, folate (up to about 100 μg) is
secreted by the liver into the bile.
• Most of this folate, however, is reabsorbed following
enterohepatic recirculation, so losses in the stool are
minimal.
Folate in pregnancy
• During the 1980s a considerable body of evidence
accumulated that spina bifida and other neural
tube defects (which occur in about 0.75–1% of
pregnancies) were associated with low intakes of
folate, and that increased intake during
pregnancy might be protective.
• It is now established that supplements of folate
significantly reduce the incidence of neural tube
defects, and it is recommended that intakes be
increased by 400 μg/day before conception.
Folate and cancer
• There is evidence that some cancers (and
especially colorectal cancer) are associated with
low folate status.
• A number of small studies have suggested that
folate supplements may be protective against
colorectal cancer, but no results from large-scale
randomized controlled trials have yet been
reported, and to date there is no evidence of a
decrease in colorectal cancer in countries where
folate enrichment of flour is mandatory.
INTERACTIONS WITH OTHER NUTRIENTS
• A relationship exists between folate and vitamin
B12 (cobalamin).
• Without vitamin B12 the methyl group from 5methyl THF can’t be removed and thus is trapped,
is sometimes called the (methyl-folate trap).
• With adequate vitaminB12 status, the convention
of Hcy to Meth is going well, which is resulting
THF, that converted into other coenzyme forms.
5-methyl THF is required for
Folate deficiency: megaloblastic anemia
• Dietary deficiency of folic acid is common and,
leads to functional folic acid deficiency.
• The cells of the bone marrow that form red
blood cells, the cells of the intestinal mucosa
and the hair follicles.
• Clinically, folate deficiency leads to
megaloblastic anemia, the release into the
circulation of immature precursors of red
blood cells.
Folate deficiency: megaloblastic anemia
• Megaloblastic anemia is also seen in vitamin B12
deficiency, where it is due to functional folate
deficiency as a result of trapping folate as methyltetrahydrofolate.
• However, the neurological degeneration of
pernicious anemia is rarely seen in folate
deficiency, and indeed a high intake of folate can
mask the development of megaloblastic anemia
in vitamin B12 deficiency, so that the presenting
sign is irreversible nerve damage.
Folate requirements
• Folate equivalents are used in RDA for dietary folate
intakes, because of differences in efficiency of folate
absorbtion from foods versus folic acid (supplements
and fortified products).
• According to the 1998 RDAs
• For adults 400 µg dietary folate requirements (DFE)/d
• Pregnancy 600 µg DFE/d
• Lactation
500 µg DFE/d
• The center for Disease Control and Prevention (CDC)
for women 400 µg synthetic folic acid /day for NTD
prevention.
TOXICITY
• Toxicity of oral folic acid in moderate doses reportedly is
virtually nonexistent.
• Folate intakes of up to 15 mg daily are problematic, include
insomnia, malaise, irritability, and gastrointestinal distress.
• A tolerable upper intake level for adults of 1,000 μg (1 mg)
for synthetic folic acid in supplements or from fortified
foods (not natural foods) has been suggested based on the
ability of folate to mask the neurological manifestations of
vitamin B12 deficiency.
• Use of folic acid supplements is usually discouraged for
some people, such as those with cancer receiving
chemotherapy with methotrexate.