Vitamin B12/Folate Absorption and Metabolism

Question 1

What can cause megaloblastic anemia?

Answer 1

Deficiency of vitamin B12 and folate can
cause a severe anemia called
megaloblastic anemia

This is an anemia that occurs as a result of
retarded synthesis of DNA in the
developing red cell in the bone marrow
•
Continual DNA synthesis is required for
production of numerous erythroblasts

Question 2

What is Erythropoiesis?

Answer 2

Erythropoiesis (from Greek ‘erythro’ meaning “red” and ‘poiesis’ meaning “to make”) is the process which produces red blood cells (erythrocytes). It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin.

Question 3

What is the result of Megaloblastic anemias?

Answer 3

Megaloblastic anemias are the result of abnormal DNA synthesis and a nuclear maturation defect
•
Erythroid precursors are stuck in the bone marrow trying to mature –
resulting in megaloblastic, hyperplasia marrow smears.

Question 4

What happens when Vit B12 or Folate are low?

Answer 4

• Decreased B12 or folate prevents synthesis of adequate amounts of DNA
• Prevents maturation and leads to megaloblastic anemia

Question 5

Information about Megaloblastic Macrocytic Anemia

Answer 5

•
Macrocytic anemias are characterized
by large erythrocytes
–
MCV >100 fL (as high as 140 fL); normal = 80-100
•
However they have normal hemoglobin content in relation to size (MCHC: mean
cell hemoglobin content)
•
Clinical presentaton: lethargy, weakness, yellow or waxy pallor, loss
of weight & appetite, diarrhea

Question 6

Why are they called Megaloblastic Anemia? What is a Megaloblast?

Answer 6

• Megaloblastic anemias are characterized by
large erythroid precursors: megaloblasts
• Decrease in mitotic divisions
• Nuclear development delayed
• However cytoplasmic volume continues to
expand

Question 7

What is the active form of Folate?

Answer 7

• Folate can exist as Dihydrofolate (FH2)
• DHF = dietary folic acid
• Reduced to THF by dihydrofolate reductase and
• Tetrahydrofolate (THF) is the active form

– 4 H + reduction of pteridine ring
– Function of THF is to transfer carbon units (e.g. CH3 groups)
from donors to acceptors
–
Serves a vital role in DNA synthesis

Question 8

What converts Dihydrofolate to Tetrahydrofolate?

Answer 8

DHF reductase

• The THF can then be converted N 5,10-methylene THF
• N 5,10-methylene THF can be used to convert Deoxyuridylate to Deoxythymidylate for usage to make DNA.

*The main carbon transfer occurs when the carbon side
chain of serine is transferred to THF to form N5,10-methylene-THF

*The carbon of N5,10-methylene-THF is then transferred to
deoxyuridylate (dUMP) to form deoxythymidylate (dTMP)
during which dihydrofolate (DHF) is formed which is
reduced by dihydrofolate reductase to THF to start cycle
again

Question 9

What is the main purpose of Folate Metabolism?

Answer 9

•The main carbon transfer occurs when the carbon side chain of serine is
transferred to THF to form N5,10-methylene-THF

•The carbon of N5,10-methylene-THF is
then transferred to deoxyuridylate
(dUMP) to form deoxythymidylate
(dTMP) during which dihydrofolate
(DHF) is formed which is reduced by
dihydrofolate reductase to THF to start
cycle again

Question 10

What is the most common cause of folate deficiency?

Answer 10

The most common cause of folate deficiency
is inadequate dietary intake of DHF.

• Usually the poor and elderly suffer from this
deficiency because diet is poor (not much
folate in junk food) – “the mom story”

• Folate deficiency also occurs in alcoholics –
most daily calories is from alcohol in which there is little folate
• Other reasons for deficiency include malabsorption (diseases of GI tract), increased requirement (pregnancy-neural tube defects) and interference from drugs.

Question 11

What is the primary form of circulating folate in the system?

Answer 11

• Start with absorption of folic acid (DHF)
• Once absorbed in the intestine, folic acid is reduced to N5-methyl-THF

•This is the primary circulating form of THF in the
bloodstream

Question 12

How is folic acid transported?

Answer 12

•N5-methyl-THF binds to receptor and goes into cells
from the circulation

• 2 proteins needed for transport of folate into cells

• N5-methyl-THF binds to “high affinity folate receptors”
which concentrates folates into vesicles

• A “membrane folate transporter” transfers N5-methyl-THF from the vesicles to the cytosol

Question 13

Why do we need Vit B12 in this pathway?

Answer 13

• folate is available as an N5-methyl-THF (CH2 binds to 1 N not both N5 and N10)
• N5-methyl-THF will not give up single methylene group to dUMP to make dTMP (for DNA synthesis)
• Something needs to happen!!

•an N5-methyl-THF needs to be de-methylated to enter
folic acid cycle as THF

•N5-methyl-THF requires vitamin B12 (cobalamin) to
become demethylated

• If B12 not available then folate stuck as N5-methyl-THF :
called the folate trap

• Vitamin B12 removes methyl group from N5-methyl-THF to make methyl cobalamin(B12-CH3) and release THF (FH4)