Folate

Folate
 B vitamin; also known as folic acid, folacin, or
pteroylglutamic (tare-o-EEL-glue- TAM-ick) acid
(PGA). The coenzyme forms are
DHF(dihydrofolate) and THF (tetrahydrofolate).
B-vitamin folate comes from the Latin word
folium, meaning “leaf.”
leafy green vegetables are excellent sources
The term folic acid refers to the synthetic form of
the vitamin found in supplements and fortified
foods
Its primary coenzyme form, THF (tetrahydrofolate),
serves as part of an enzyme complex that transfers 1-
carbon compounds that arise during metabolism.
This action convert vitamin B12 to one of its
coenzyme forms, synthesizes the DNA required for all
rapidly growing cells, and regenerates the amino acid
methionine from homocysteine.
 Folate
 Folate consists of 3 parts: pteridine, paraaminobenzoic acid
(PABA), & 1 or more molecules of the a.a. glutamic acid,
glutamate
 Folate monoglutamate
 In food, about 90% of the folate molecules have 3 or more
glutamates attached to the carboxyl group (red asterisk in the
structure) and are known as polyglutamates.
 Folate Sources
 Foods that have the largest amount and
most bioavailable folate are liver,
legumes, and leafy green vegetables
 Other, rich sources of folate include
avocados, lentils and oranges.
 Bread and cereal products from milled
grains are fortified with folic acid, making
them good sources of this vitamin
 Ready-to-eat cereals, bread, legumes,
orange and grapefruit juice, lettuce, milk,
and potatoes are leading sources
 Food processing and preparation can RDA for adult women and men: 400µg
destroy 50 to 90% of the folate in food. The UL for synthetic folic acid is set at
 Folate is extremely susceptible to 1000 μg (1 mg); intakes above this level
may mask a vitamin B-12 deficiency.
destruction by heat, oxidation, and The UL does not apply to folate in foods
ultraviolet light
 Folate Digestion and absorption
 The small intestine prefers to absorb the “free”
folate form—the monoglutamate
 Enzymes (folate conjugases) on the intestinal
cell surfaces hydrolyze the polyglutamate to
monoglutamate
 Then monoglutamate is attached to a methyl
group
 Special transport systems deliver the
monoglutamate with its CH3 group to the liver
and other body cells
 For folate coenzyme to function, the CH3
must be removed by an enzyme that requires
the help of B12
 Without that help, folate becomes trapped
inside cells in its methyl form, unavailable to
support DNA synthesis and cell growth
 Folate Digestion and absorption
 To dispose of excess folate, enterohepatic
circulation
 Folate is vulnerable to GI tract injuries
 Folate has to be reabsorbed repeatedly. If the GI
tract cells are damaged, then folate is rapidly lost
from the body
 Alcohol abuse; folate deficiency rapidly
develops
 The folate coenzymes are active in cell
multiplication—and the cells lining the GI tract
are among the most rapidly renewed cells in
the body. When unable to make new cells, the GI
tract deteriorates and not only loses folate, but
also fails to absorb other nutrients.
 Folate _ Functions
 Folate coenzymes are required for the synthesis and maintenance of new
cells.
 Folate coenzymes function in metabolic pathways in which single carbon
groups are exchanged.
 The folate coenzymes are formed from a central coenzyme form called
tetrahydrofolic acid (THFA). Folate coenzymes are critical for DNA
synthesis, and amino acid metabolism.
 Folate _ Functions
DNA Synthesis
 THFA is required for the synthesis of DNA, which contains 4 nitrogenous
bases: cytosine and thymine (pyrimidines) & adenine and guanine (purines)
 The pyrimidine thymine is formed by the addition of a methylene group
(CH2) to the pyrimidine uracil.
 A folate coenzyme supplies the CH2 .
 Folate and vitamin B-12 function are closely linked. A vitamin B-12
coenzyme is required to recycle the folate coenzyme needed for DNA
synthesis
 Thus, folate and vitamin B-12 deficiencies can produce identical signs and
symptoms.
 THFA also is needed for the synthesis of the purines in DNA.
 Thus, DNA synthesis and repair may decline in a folate shortage.
 Folate and cancer
 The cancer drug methotrexate takes advantage of the key role of
THFA in DNA synthesis. Methotrexate, as folate antagonist,
interferes with THFA metabolism
 This, in turn, reduces DNA synthesis throughout the body. This
reduction in DNA synthesis can halt the growth of cancer cells,
but it also affects other rapidly proliferating cells, such as
intestinal and red blood cells.
 The typical side effects of methotrexate therapy are the same as
for a folate deficiency (e.g., diarrhea and anemia).
 Individuals treated with methotrexate are sometimes advised to
take supplemental folic acid to reduce the drug’s toxic side effects.
 This supplementation probably does not influence the
effectiveness of methotrexate.
Folate and Heart Diseases
 Research indicates that high levels of the homocysteine
and low levels of folate increase the risk of fatal heart
disease.
 One of folate’s key roles in the body is to break down
homocys- teine. Without folate, homocysteine accumulates,
which seems to enhance blood clot formation and arterial
wall deterioration.
 Fortified foods and folate supplements raise blood folate
and reduce blood homocysteine levels to an extent that may
help to prevent heart disease.
 Supplements do not seem to reduce the risk of death from
cardiovascular causes
 Folate _ Functions
Amino Acid Metabolism and Other Functions
 THFA is important in amino acid metabolism, especially the
inter-conversions of amino acids.
 It accepts 1-carbon groups from various amino acids and is
responsible for converting the a.a. glycine to the a.a. serine
(main source of methyl groups for THFA) and converting the
essential a.a. histidine to the a.a. Glutamatic acid.
 THFA, along with vitamin B-12, is involved in a pathway that
converts the amino acid homocysteine to the amino acid
methionine.
 Another key function of folate is the formation of
neurotransmitters in the brain.
Folate Deficiency
 Folate deficiency can result from
 low intake,
 inadequate absorption (often associated with alcoholism),
 increased need (most commonly occurring in pregnancy) (600 μg
DFE/day),
 compromised utilization (typically associated with vitamin B-12
deficiency),
 the use of certain chemotherapy medications, e.g. Methotrexate
 excessive excretion (linked to long-standing diarrhea).
 Pregnant women require extra folate because of the
increased rate of cell division, and thus of DNA synthesis, in
their own bodies and in the developing fetus
 Folate Deficiency
 A deficiency of folate first affects cell types that are actively synthesizing
DNA because these cells have a short life span and rapid turnover rate.
 For instance, red blood cells have a 120-day life span and are vulnerable to
folate deficiency.
 Without folate, precursor cells in the bone marrow cannot form new DNA
and therefore cannot divide normally to become mature red blood cells. The
cells grow larger because there is continuous formation of RNA, leading to
the increased synthesis of protein and other cell components.
 Unlike normal mature red blood cells, these cells (called megaloblasts)
retain their nuclei and remain in a large, immature form.
 Any of these large cells that do enter the bloodstream are called
macrocytes. Their presence results in a form of anemia called
megaloblastic, or macrocytic, anemia
 Folate Deficiency
 Large, immature cells also appear throughout the
GI tract during chronic folate deficiency.
 This occurs because DNA synthesis is impaired,
which hinders cell division in the GI tract. This
change contributes to a decreased absorptive
capacity of the GI tract and persistent diarrhea.

 White blood cell synthesis also is disrupted by a

folate deficiency because these cells are made in
rapid bursts during immune challenges (e.g.,
infections). Thus, immune function can be
diminished during a folate deficiency.
Folate Deficiency Steps
 Folate _ Neural Tube Defects
 A maternal deficiency of folate and a genetic predisposition have been linked
to the development of neural tube defects in the fetus
 These defects include spina bifida (a spinal cord or spinal fluid bulge through
the back) and anencephaly (the absence of a brain)
 In both cases, there is a defect in the very early development of the neural tube,
the structure that subsequently forms the brain, spinal cord, spinal nerves, and
spinal column.

Victims of spina bifida may exhibit paralysis,

incontinence, hydrocephalus (the abnormal buildup of
spinal fluid in the brain), and learning disabilities.
Children born with anencephaly (absence of major
portion of brain) die shortly after birth.
Folate _ Neural Tube Defects
 Folate is critical to normal neural tube development. The neural tube
forms and closes very early in pregnancy—the first 21 to 28 days after
conception.
 During this time of critical development, many women are unaware
that they are pregnant. Thus, ensuring good folate status for all women
capable of becoming pregnant is critical
 Before fortification, about 4000 pregnancies per year were affected by
a Neural Tube Defect in USA
 Since fortification, the number of babies born with a neural tube defect
has decreased by a third
 Women who have had a child with a neural tube defect are advised to
consume 4 mg/day of folic acid beginning at least 1 month before any
future pregnancy. This must be done under strict physician supervision.