Folate: Structure, Sources, and Bioavailability
F
o
l
a
t
e
•
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
.
F
o
l
a
t
e
s
t
r
u
c
t
u
r
e
•
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.
F
o
l
i
c
A
c
i
d
-
F
o
l
a
t
e
(
P
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t
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m
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)
S
o
u
r
c
e
s
•
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.
S
o
u
r
c
e
s
S
o
u
r
c
e
s
•
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 folate-
binding-protein, which appears to enhance its
bioavailability.
D
I
G
E
S
T
I
O
N
,
A
B
S
O
R
P
T
I
O
N
,
T
R
A
N
S
P
O
R
T
,
A
N
D
S
T
O
R
A
G
E
•
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
.
A
b
s
o
r
p
t
i
o
n
•
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.
T
r
a
n
s
p
o
r
t
a
n
d
S
t
o
r
a
g
e
•
Free in plasma:
monoglyutamate derivatives, mainly THF.
•
Uptake by the liver using carrier and converted to 5-methyl THF and 10-
formyl-THF (tightly formulated).
•
33% as THF, 37% as 5-methyl THF, 23% as 10-formyl THF and 7% as 5-
formyl 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
T
r
a
n
s
p
o
r
t
a
n
d
s
t
o
r
a
g
e
•
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 (2-
3mo)
folate status
than dose plasma.
T
i
s
s
u
e
d
i
s
t
r
i
b
u
t
i
o
n
•
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
F
U
N
C
T
I
O
N
S
A
N
D
M
E
C
H
A
N
I
S
M
S
O
F
A
C
T
I
O
N
•
THF functions in the body as
a coenzyme
in both
the mitochondria and cytoplasm to accept
one-
carbon 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.
F
U
N
C
T
I
O
N
S
A
N
D
M
E
C
H
A
N
I
S
M
S
O
F
A
C
T
I
O
N
•
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.
•
The THF derivatives, which participate in a
variety of reactions, are illustrated as follows:
F
U
N
C
T
I
O
N
S
A
N
D
M
E
C
H
A
N
I
S
M
S
O
F
A
C
T
I
O
N
•
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.
F
u
n
c
t
i
o
n
a
n
d
m
e
c
h
a
n
i
s
m
o
f
a
c
t
i
o
n
A
m
i
n
o
a
c
i
d
m
e
t
a
b
o
l
i
s
m
M
E
T
A
B
O
L
I
S
M
A
N
D
E
X
C
R
E
T
I
O
N
•
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
.
•
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 μ
g/day
before conception.
F
o
l
a
t
e
i
n
p
r
e
g
n
a
n
c
y
F
o
l
a
t
e
a
n
d
c
a
n
c
e
r
•
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.
I
N
T
E
R
A
C
T
I
O
N
S
W
I
T
H
O
T
H
E
R
N
U
T
R
I
E
N
T
S
•
A relationship exists
between
folate
and
vitamin
B
12
(cobalamin).
•
Without vitamin B12 the methyl group from 5-
methyl THF can’t be removed and thus is trapped,
is sometimes called the (methyl-folate trap).
•
With adequate vitamin
B
12
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
F
o
l
a
t
e
d
e
f
i
c
i
e
n
c
y
:
m
e
g
a
l
o
b
l
a
s
t
i
c
a
n
e
m
i
a
•
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.
F
o
l
a
t
e
d
e
f
i
c
i
e
n
c
y
:
m
e
g
a
l
o
b
l
a
s
t
i
c
a
n
e
m
i
a
•
Megaloblastic anemia is also seen in vitamin B12
deficiency, where it is due to functional folate
deficiency as a result of trapping folate as methyl-
tetrahydrofolate.
•
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.
F
o
l
a
t
e
r
e
q
u
i
r
e
m
e
n
t
s
•
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.
T
O
X
I
C
I
T
Y
•
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.
Folate, also known as vitamin B9, plays a crucial role in various bodily functions. Folic acid and folate are different forms of the vitamin, with distinct sources and structures. Good food sources of folate include green vegetables, legumes, fruits, and fortified products. The bioavailability of folate from foods varies due to factors like pH, enzymatic activity, and dietary constituents. The structure of folate consists of three essential parts needed for vitamin activity, emphasizing its importance in overall health.
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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 g 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 https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcRpmid1GfOz_jHJqWyh-WlvEb5N0kHf_v0bn3GD2oji9S2CrP2m
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 folate- binding-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 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 10- formyl-THF (tightly formulated). 33% as THF, 37% as 5-methyl THF, 23% as 10-formyl THF and 7% as 5- formyl 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 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 (2- 3mo) folate status than dose plasma.
Tissue distribution 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 one- carbon 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 g) 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 g/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 5- methyl 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 methyl- tetrahydrofolate. 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 g dietary folate requirements (DFE)/d Pregnancy 600 g DFE/d Lactation 500 g DFE/d The center for Disease Control and Prevention (CDC) for women 400 g 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 g (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.
