Folate and Vitamin B12

Question 1

What is the main circulating form of folate?

Answer 1

Monoglutamate N5-FH4

Question 2

What is the action of methotrexate?

Answer 2

Analog of folate, it is a competitive inhibitor of dihydrofolate reductase, a key enzyme in pyrimidine biosynthesis

Question 3

What is the significance of folate in cancer treatment?

Answer 3

Inducing folate deficiency will inhibit DNA synthesis due to its role in purine/pyrimidine synthesis

Question 4

What are megaloblasts?

Answer 4

They are large cells that is unable to divide due to the lack of folate. Cells are unable to mature. In the case of RBCs, they retain their nucleus

Question 5

What can cause folate deficiency?

Answer 5

Alcoholism (Inadequate absorption)
Folic acid antagonists (e.g. methotrexate, trimethoprim)
Oral contraceptives
Low dietary intake
Infection with giardia
Celiac Sprue
Pregnancy/Psoriasis (Increased requirement)
Old age
Compromised utilization (Vit. B12 deficiency)
Excessive excretion (long-standing diarrhea)

Question 6

What two other drugs have similar actions to methotrexate?

Answer 6

Aminopterin and trimethoprim

Question 7

What enzyme does 5-fluorouracil block? What is the role of that enzyme?

Answer 7

It blocks thymidylate synthase. It blocks the conversion of dUMP to dTMP

Question 8

What is the action of dihydrofolate reductase (DHFR)?

Answer 8

Catalyzes both the reactions going from folate to tetrahydrofolate

Question 9

What can be the deficiency of vitamin B12 (cobolamin) cause?

Answer 9

Pernicious anemia, dietary sources are liver, kidney, egg, and cheese

Question 10

What are the three active forms of folate? What are their functions?

Answer 10

N5Met FH4
N10 formyl FH4 (purine synthesis)
N5,N10-methylene FH4 (pyrimidine synthesis)

Question 11

What is free vitamin B12 bound to? What synthesizes this protein?

Answer 11

R-protein (transcobolamin-I/haptocorrins) synthesized by the gastric mucosa in the stomach

Question 12

Where does R-protein-vitamin B12 complex travel to?

Answer 12

R-protein-vitamin B12 complex travels to the small intestine

Question 13

What is the action of the pancreatic protease, trypsin?

Answer 13

It releases vitamin B12 intrinsic factor (IF), a glycoprotein produced by parietal cells in the stomach, binds to vitamin B12

Question 14

Where does the intrinsic factor vitamin B12 complex travel to? What does it do?

Answer 14

To the ileum where the complex binds to a receptor for absorption

Question 15

What happens to vitamin B12 in intestinal cells? What does it attach to?

Answer 15

In the enterocytes, B12 attaches to transcobalamin II (TCII) to enter the portal blood. Vitamin B12 will be taken up by liver, bone marrow, and RBC

Question 16

Explain the path of dietary B12 through the digestive system starting from the stomach all the way to the ileum

Answer 16

Dietary B12 that enter the stomach will be bound to R-binders (haptcorrins) and travel to the intestine where the R-binders will be destroyed by pancreatic proteases. The freed B12 then binds to intrinsic factor (IF). B12 is absorbed by the ileum and carried by proteins named transcobolamins (TC) to the liver, where B12 is stored

Question 17

Vitamin B12 is required for what two conversion reactions?

Answer 17

Methylmalonyl CoA —> succinyl CoA — assay (Schelling test) for vitamin B12 deficiency is based on the above reaction

Homocysteine —> Met in a reaction catalyzed by methionine synthase/homocysteine

Question 18

What is the methyl donor in methionine synthesis?

Answer 18

methyltetrahydrofolate (MTHF), this reaction frees THF to participate in DNA synthesis

Question 19

What is the cause of pernicious anemia?

Answer 19

The cause of pernicious anemia is true vitamin B12 deficiency resulting from hampered absorption of the vitamin — due to the lack of the availability of the intrinsic factor

Question 20

What are some of the causes of true vitamin B12 deficiency?

Answer 20

Absence of intrinsic factor (IF)
Absence or defective synthesis of pancreatic proteases
Bacterial overgrowth in the small intestine
Tapeworm infestation
Use of certain antiulcer medications (reduction of acid synthesis)
Chronic malabsorption syndromes (AIDS)
Chronic pancreatic disease
Absence or surgical removal of much or all of the ileum and stomach
Crohn’s disease (Crohn ileitis)

Question 21

What are some of the dietary sources of vitamin B12?

Answer 21

Most nutrient-dense sources of vitamin B12 — organ meats (liver, kidneys, heart), seafood, beef, eggs, hotdogs (contain organ meat scraps), ham, milk and milk products

Question 22

What can be used to treat vitamin B12 deficiency?

Answer 22

Three possible types for patients with defective vitamin B12 absorption: monthly injection, use of a vitamin B12 nasal gel, weekly ingestion of vitamin B12 supplement with megadoses (300 x RDA)

Question 23

What are other clinical symptoms of vitamin B12 deficiency?

Answer 23

Vitamin B12 deficiency causes nerve degeneration producing — sensory disturbances in the legs (tingling and numbness), paresthesia (burning and prickling — neurological disease only when chronic, loss of concentration and memory, visual disturbances, disorientation, dementia, sore tongue, in the worst cases, loss of bowel and bladder control

Question 24

How can an increase in homocysteine lead to atherosclerosis?

Answer 24

High homocysteine is linked to neurological and cardiovascular diseases. Inhibition of glutathione peroxidase leads to low glutathione, which leads to increased oxidized LDL resulting in atherosclerosis

Question 25

How does high homocysteine occur?

Answer 25

Cystathionine —> cysteine —> accumulation of cysteine —> inhibition of cystathione synthesis —> homocysteine accumulation —> release in the bloodstream

Question 26

What can lead to the defect of neural tubes in the fetus? How can it be prevented?

Answer 26

The deficiency of the coenzyme form of folate during pregnancy has been linked to a high risk of neural tube defects in the fetus

The intake of folate supplement before conception, and at least 1 month after conception, decreases the risk of neural tube defects

Question 27

Mutation in N5,N10 methylene-FH4 reductase can cause what?

Answer 27

Mutation in N5,N10 methylene-FH4 reductase causes an elevation of homocusteine secondary to folate deficiency (N5-methyl-FH4 levels decrease). This mutation makes the enzyme thermolabile, thereby leading to the inhibition of DNA synthesis

Question 28

What inhibits folate absorption?

Answer 28

Anticonvulsants

Question 29

What is elevated in vitamin B12 deficiency and what is elevated in folate deficiency?

Answer 29

In B12 deficiency, both methylmalonic acid and homocysteine are elevated in serum while only homocysteine is elevated in folate

Question 30

What cells produce intrinsic factor?

Answer 30

Gastric parietal cells

Question 31

Explain THF trap. What can the deficiency of vitamin B12 lead to?

Answer 31

Starts out from homocysteine and ends in methionine. In the absence of vitamin B12, THF is trapped in a methyl-bound form N5-MTHF. The absence of vitamin B12 can eventually lead to secondary folate deficiency

Question 32

What can homocysteine be turned into?

Answer 32

It can be methylated to form methionine or condensed to form cystathionine

Question 33

How is the risk of neural tube defects decreased?

Answer 33

The intake of folate supplement before conception, and at least 1 month after conception