MMT: folate metabolism

Question 1

What is folic acid?

Answer 1

Vitamin B9

Question 2

What are the 3 components of folic acid?

Answer 2

Pteridine ring, aminobenzoate ring, and at least one glutamate

Question 3

Is folate an essential vitamin?

Answer 3

Yes! We can make all of the individual components but cannot facilitate the joining of the pteridine ring and aminobenzoate

Question 4

What is the active form of folate?

Answer 4

THF (tetrahydrofolate)

Question 5

What is polyglutamination?

Answer 5

More than one glutamate residue attached to the folate molecule, linked via a-amino and y-carboxyl groups

Question 6

What is necessary for absorption of folate?

Answer 6

They can only have one glutamate residue; after absorption it can re-undergo polyglutamination

Question 7

How much folate do people over 14 need?

Answer 7

400ug

Question 8

How much folate do pregnant people need?

Answer 8

800ug

Question 9

What is dihydrofolate reductase?

Answer 9

Converts folic acid to THF so it can be utilized in the body! It adds 4 hydrogen atoms to folic acid in order to form THF in 2 separate reactions

Question 10

What molecule is required for dihydrofolate reductase to carry out its function?

Answer 10

NADPH

Question 11

Where does the molecule utilized by dihydrofolate reductase come from?

Answer 11

NADPH from the pentose phosphate pathway!

Question 12

What is the next step of folate metabolism once we have THF?

Answer 12

It picks up a methylene group to form 5,10-methylene THF

Question 13

What does thymidine synthase do?

Answer 13

Utilizes 5,10-methylene THF to convert dUMP to TMP and reform dihydrofolate

Question 14

What does methylene THF reductase do?

Answer 14

Convert 5,10-methylene THF to 5-methyl THF

Question 15

What is 5-methyl THF used for?

Answer 15

Synthesis of methionine from homocysteine via methionine synthase; THF is reformed in this process

Question 16

What is 10 formyl THF?

Answer 16

Used in purine biosynthesis! Process reforms THF

Question 17

What is 5-formimino THF?

Answer 17

Formed during histidine degradation; it can be deaminated to form 5,10-methenyl THF that can become 5,10-methylene THF or 10 formyl THF

Question 18

What amino acids donate methylene groups to THF?

Answer 18

Serine and glycine

Question 19

What amino acids donate a formimino group to THF?

Answer 19

Histidine

Question 20

What amino acids donate a formyl group to THF?

Answer 20

Tryptophan (indirectly)

Question 21

Describe the role of THF in the conversion of serine to glycine.

Answer 21

THF is utilized in the conversion, and 5,10-methylene THF is formed as a result

Question 22

Describe the role of THF in histidine degradation.

Answer 22

FIGLU is formed in the process, which is acted on by formiminotransferase to form glutamate. In this process, the formimino group is transferred to THF to form 5-formimino THF

Question 23

What is FIGLU used for?

Answer 23

Testing for folate deficiency! We load someone with histidine and monitor FIGLU. If we don’t have enough folate, FIGLU builds up

Question 24

What is SAM?

Answer 24

A really important methyl donor generated in the methionine cycle

Question 25

Describe the role of THF in methionine regeneration.

Answer 25

5-methyl THF passes a methyl group to B12, which then donates it to homocysteine to reform methionine.

Question 26

A person has a buildup of homocysteine. What might be deficient?

Answer 26

B12 or 5-methyl THF

Question 27

What is the distinguishing symptom between 5-methyl THF and B12 deficiency in homocysteine buildup?

Answer 27

Neurological effects! These present with B12

Question 28

What happens with folate if we have a methionine synthase deficiency?

Answer 28

5-methyl THF accumulates and gets trapped in that form, keeping us from reforming other versions of folate. This essentially creates a functional folate deficiency and presents as folate deficiency and homocystinuria

Question 29

What happens if we have a 5,10-methylene THF reductase deficiency?

Answer 29

We cannot convert 5,10-methylene THF to 5-methyl THF, which is necessary to convert homocysteine to methionine. This results in homocystinuria, but no trapping of folate. There won’t be evidence of functional folate deficiency

Question 30

Describe the role of THF in purine biosynthesis.

Answer 30

The 10-formyl THF form is required in 2 steps in order to synthesize purines

Question 31

Describe the role of THF in thymidylate synthesis.

Answer 31

The 5,10-methylene THF is utilized as a cofactor by thymidylate synthase to convert dUMP to dTMP

Question 32

What form of folate is formed via thymidylate synthase?

Answer 32

Dihydrofolate

Question 33

What are benefits of folate during pregnancy?

Answer 33

Reduces risk of cleft lip, congenital malformations, neural tube defects, UTI, etc

Question 34

What is folate protective against?

Answer 34

Stroke, colon cancer, and macula degeneration. These can all be related to homocystinuria, which can be prevented by adequate folate

Question 35

What are presentations of folate deficiency?

Answer 35

Megaloblastic anemia, weakness, behavior disorders

Question 36

Describe fluorouracil in relation to folate.

Answer 36

It will compete with folate for thymidylate synthase in the conversion of dUMP to dTMP. Cancer cells use this process, so the fluorouracil causes suicide inhibition and messes up the process

Question 37

What folate-related enzymes are targets for chemo?

Answer 37

Thymidylate synthase and dihydrofolate reductase

Question 38

Describe chemo and dihydrofolate reductase.

Answer 38

Aminopterin and methotrexate competitively bind in dihydrofolate reductase, preventing formation of THF. This impacts DNA synthesis which helps control the tumor

Question 39

What supplement do we take with methotrexate?

Answer 39

5-formyl THF to prevent folate deficiency; cancer cells aren’t good at taking this up but our normal cells can, so this allows us to starve the tumor but keep folate functioning in the patient