Metabolism of one-carbon fragments; folic acid biochemistry- Lecture 76

Question 1

Describe the reduction of folic acid consumed from the diet or ingested as a vitamin.

Answer 1

Folate (F) + NADPH < —- > dihydrofolate (FH2) + NADP+
via dihydrofolate reductase
FH2 + NADPH < —- > tetrahydrofolate (FH4/THF) + NADP+
via dihydrofolate reductase

Question 2

What is the structure of folate?

Answer 2

pteridine ring, PABA group, and glutamate

Question 3

What is the function of THF?

Answer 3

transfers single carbon atoms in several biochemical reactions

Question 4

What forms of Carbon are carried by THF?

Answer 4

methyl (-CH3)
methylene (-CH2-)
methenyl (=CH-)
formyl (N5 or N10-CHO)
formamino (N5-CH=NH)

Question 5

What is the function of methyl carrying THF?

Answer 5

N5-CH3 THF makes CH3B12 for the reaction of homocysteine to Met

Question 6

What is the function of methyenyl carrying THF?

Answer 6

N5=CH2-N10 THF makes C2 and C8 of the purine ring

note that for our purposes this is the same as the formyl and formimino carrying

Question 7

What is the function of methylene carrying THF?

Answer 7

N5-CH2-N10 THF; makes dTMP from dUMP (intermediate redox state)

Question 8

_____ is the most important CH2 donor in the folic acid pool.

Answer 8

Serine

Question 9

What are the sources of carbon atoms for folate?

Answer 9

serine
glycine
histidine

Question 10

Describe how serine donates a carbon to folate.

Answer 10

OH-CH2-CH-(NH2)COOH + THF < —- > Glycine + N5-CH2-N10-THF

via serine transhydroxymethylase

Question 11

Describe how glycine donates a carbon to folate.

Answer 11

Glycine + THF + NAD –> NH3 + CO2 + N5-CH2-N10 THF + NADH

Question 12

Describe how histidine donates a carbon to folate.

Answer 12

histidine –> –> N-fomiminoGlu (FIGLU)

FIGLU + THF –> Glu + N5-formamino-THF

Question 13

Describe the synthesis of dTMP.

Answer 13

dUMP + N5,N10methylene FH4 –> dTMP + F2 dihydrofolate
via thymidylate synthase
FH2 dihydrofolate + NADPH –> NADP+ + FH4
via dihydrofolate reductase
FH4 + serine –> glycine + N5,N10methylene FH4

Question 14

Name inhibitors in the formation of dTMP cycle.

Answer 14

5-fluoroucil inhibits thymidylate synthase

aminopterin and amethopterin (methotrexate) inhibit DHF reductase

Question 15

What is pernicious anemia?

Answer 15

deficiency of glycoprotein called “instrinsic factor” (IF) needed for absorbtion of B12, leading to a disturbance in folate metabolism
N5-CH3 THF accumulates if no B12 causing other forms of folate (methenyl, methylene) to decrease because the reaction is irreversible
often occurs with age because IF is lost as people get older

Question 16

How is pernicious anemia treated?

Answer 16

vitamin B12 (normally via intramuscular injections every 3 months)