FOLIC ACID METABOLISM

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FOLIC ACID METABOLISM
Dr. Songyot Anuchapreeda Department of Clinical
Microscopy Faculty of Associated Medical
Sciences Chiang Mai University AMS 501701
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Functions New cell synthesis. Deficiency
Diseases Megaloblastic anemia Symptoms Anemia,
red tongue, nervous disorders, and
confusion. Toxicity None reported Average RDA
50 - 200 mg/day Sources Beans, grains,
liver. Dietary Folate Equivalent Synthetic
Folate added to foods is absorbed more quickly
than folate naturally occurring in foods. Hence,
Dietary Folate Equivalent (DFE) has been created,
to permit more accurate assessment of deliverable
folate in the diet. DFE mg food folate (1.7
X mg synthetic folate).
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Structure of folic acid Folic acid consists of
a pteridine base attached to p-aminobenzoic acid
and glutamic acid. Animals cannot make
p-aminobenzoic acid or attach glutamic acid to
aminobenzoic acid and all our folic acid is
ultimately derived from microbial and plant
sources. The structure of folic acid is shown
below (after uptake into the cell additional
glutamic acid residues may be added to the one
already present. Folic acid carrying polyglutamic
acid cannot be transported back out of the cell)
Pteroic acid
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Activation of folic acid Folic acid is not the
active form of the vitamin. Once in our cells
folic acid undergoes 2 successive reductions to
give the active form - tetrahydrofolate
(H4folate). Just the "business" part of the folic
acid is shown for ease of illustration
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Function of folic acid Tetrahydrofolate is a
coenzyme in many reactions involving the transfer
of chemical groups containing 1 carbon atom to
other compounds (one carbon metabolism). The
single carbon groups can be carried on N5, N10 or
bridged between both these nitrogens
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???????????????????????? purine
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????????????? pyrimidine nucleotide
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????????????? purine nucleotide
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Homocysteine is produced by the demthylation of
methionine. The amino acid is then recycled back
to methionine when folate donates a methyl group,
with vitamin B12 acting as a cofactor.
Homocysteine can also be recycled to methionine
with the help of betaine or choline.
Alternatively, homocysteine can be converted to
cysteine in a process requiring vitamin B12.
Deficiency in any of these pathways can lead to
buildup of homocysteine. SAM s-adenosyl
methionine.
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Methionine synthesis
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We have already looked at the following reaction
involving N5-methyl-tetrahydrofolate in relation
to vitamin B12 biochemistry. N5-Methyl-tetrahydrof
olate Homocysteine Tetrahydrofolate
Methionine Remember this is the only reaction
that can regenerate tetrahydrofolate from
N5-methyl-tetrahydrofolate. Without it all the
tetrahydrofolate will eventually end up trapped
as N5-methyl-tetrahydrofolate and the other forms
shown above will be unavailable.
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Another very important reaction involves the
synthesis of deoxythymidylate (dTMP), one of the
four deoxyribonucleotides required for DNA
synthesis. In this reaction N5,N10-methylene
tetrahydrofolate transfers a methyl group to
deoxyyuridylate (dUMP) to form dTMP
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Megaloblastic anaemia and folic acid
deficiency Megaloblastic anaemia was mentioned
in relation to vitamin B12 deficiency above. The
mechanism of this disease should now be clear to
you - folic acid deficiency reduces the capacity
of the body to make dTMP which affects the
rapidly dividing bone marrow cells associated
with red blood cell production. Remember that
pernicious anaemia is due to a primary deficiency
of vitamin B12 which leads to a secondary
deficiency of folic acid because all the folate
ends up trapped as N5-methyl-tetrahydrofolate due
to lack of vitamin B12 coenzyme needs by
methionine synthase.
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Folate Vignette Recently, we have come to
understand that folate deficiency in pregnant
women can lead to neural tube defects. Neural
tube defects are characterized by lack of proper
development of the spinal cord, ranging from
slight spinal problems all the way to
anencephaly, a birth defect that results in
babies being born without a brain. Folate is
named after foliage, where it is found in
abundance. A sound diet, with the recommended
servings from the vegetable group, will guard
against neural tube defects
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Sulphanilamide blocks incorporation of
p-aminobenzoic acid into folateSulphanilamide
was one of the first antibacterial drugs.
Sulphanilamide is structurally similar to
p-aminobenzoic acid and inhibits the enzyme
(dihydropteroate synthetase) responsible for
incorporating p-aminobenzoic acid into folic acid.
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VITAMIN B12 METABOLISM
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Functions New cell synthesis, nerve
maintenance. Deficiency Diseases Vitamin B12
deficiency anemia Symptoms Anemia, fatigue, and
paralysis. Toxicity None reported Average RDA
1 - 2 mg/day Sources Meat, milk, fish, and
poultry.
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Vitamin B12 Dietary sources and recommended
intake Vitamin B12 (cobalamin) is only
synthesized by micro-organisms. Animals obtain
the vitamin from their natural bacterial flora or
eat other animals who have stores of the vitamin
from their own flora. Milk is also a good
source. Vegans are at risk from deficiency.
RNI 1.5µg/day.
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Absorption and transport of vitamin B12
Vitamin B12 is binds to a glycoprotein (called
intrinsic factor, IF) in the stomach.
Intrinsic factor is secreted by the parietal
cells. The resulting vitamin-intrinsic factor
complex is recognizes surface receptors on the
mucosal cells of the ileum and is absorbed. It
is transported around the body bound to specific
a B12 binding protein (transcobalamin). It is
stored mainly in the liver in amounts (3-5mg)
sufficient to last a couple of years.
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DIGESTION OF VITAMIN B12
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Function of vitamin B12 Vitamin B12 (as
deoxyadenosylcobalamin) is a co-enzyme for the
enzyme methylmalonyl CoA mutase which is involved
in metabolism of odd number carbon fatty acids.
Breakdown of odd number fatty acids leaves a 3
carbon fragment propionyl CoA. This is usually
converted to citric acid cycle intermediates for
further metabolism
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• Vitamin B12 is also a coenzyme in a reaction
  involved in methionine metabolism. This
  reaction involves the transfer of a methyl group
  from a derivative of the vitamin folic acid
  (N5-methyl tetrahydrofolate or more simply
  N5-methyl-H4folate) to homocysteine to give
  methionine and is catalysed by methionine
  synthase.
• During the reaction N5-methyl-H4folate is thus
  converted back to tetrahydrofolate (H4folate).

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Methionine synthesis using Folate and B12
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Choline synthesis
B12
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Deficiency of vitamin B12 Vitamin B12
deficiency is rarely due to an absence of the
vitamin in the diet (except for vegans) but more
commonly due to an absorption problem. For
example there is an auto immune disease which
destroys the parietal cells that secrete the
intrinsic factor required for absorption. The
treatment for this disease would be life long
injections of vitamin B12 (oral administration
wouldn't be much use!)
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• The features of vitamin B12 deficiency can be
  explained very nicely by considering the
  biochemistry described above
• The impairment of methylmalonyl CoA mutase due to
  lack of vitamin B12 coenzyme causes an
  accumulation of unusual odd number carbon fatty
  acids. These fatty acids accumulate in nerve cell
  membranes resulting in irreversible neurological
  disorders.
• The impairment of methionine synthase due to lack
  of vitamin B12 coenzyme results in the body's
  supply of H4folate being trapped as
  N5-methyl-H4folate (the so called "folate trap").
  The locking away of folate in this form can lead
  to a secondary or artificial deficiency of folic
  acid. One of the main symptoms of folic acid
  deficiency is anaemia.
• If the anaemia is due to a true folic acid
  deficiency it is called megaloblastic anaemia.
• If the anaemia is due to a secondary folic acid
  deficiency caused by primary vitamin B12
  deficiency it is called pernicious anaemia.

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