Folate and Vitamin B12 Flashcards
What is the main circulating form of folate?
Monoglutamate N5-FH4
What is the action of methotrexate?
Analog of folate, it is a competitive inhibitor of dihydrofolate reductase, a key enzyme in pyrimidine biosynthesis
What is the significance of folate in cancer treatment?
Inducing folate deficiency will inhibit DNA synthesis due to its role in purine/pyrimidine synthesis
What are megaloblasts?
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
What can cause folate deficiency?
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)
What two other drugs have similar actions to methotrexate?
Aminopterin and trimethoprim
What enzyme does 5-fluorouracil block? What is the role of that enzyme?
It blocks thymidylate synthase. It blocks the conversion of dUMP to dTMP
What is the action of dihydrofolate reductase (DHFR)?
Catalyzes both the reactions going from folate to tetrahydrofolate
What can be the deficiency of vitamin B12 (cobolamin) cause?
Pernicious anemia, dietary sources are liver, kidney, egg, and cheese
What are the three active forms of folate? What are their functions?
N5Met FH4
N10 formyl FH4 (purine synthesis)
N5,N10-methylene FH4 (pyrimidine synthesis)
What is free vitamin B12 bound to? What synthesizes this protein?
R-protein (transcobolamin-I/haptocorrins) synthesized by the gastric mucosa in the stomach
Where does R-protein-vitamin B12 complex travel to?
R-protein-vitamin B12 complex travels to the small intestine
What is the action of the pancreatic protease, trypsin?
It releases vitamin B12 intrinsic factor (IF), a glycoprotein produced by parietal cells in the stomach, binds to vitamin B12
Where does the intrinsic factor vitamin B12 complex travel to? What does it do?
To the ileum where the complex binds to a receptor for absorption
What happens to vitamin B12 in intestinal cells? What does it attach to?
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
Explain the path of dietary B12 through the digestive system starting from the stomach all the way to the ileum
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
Vitamin B12 is required for what two conversion reactions?
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
What is the methyl donor in methionine synthesis?
methyltetrahydrofolate (MTHF), this reaction frees THF to participate in DNA synthesis
What is the cause of pernicious anemia?
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
What are some of the causes of true vitamin B12 deficiency?
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)
What are some of the dietary sources of vitamin B12?
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
What can be used to treat vitamin B12 deficiency?
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)
What are other clinical symptoms of vitamin B12 deficiency?
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
How can an increase in homocysteine lead to atherosclerosis?
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
How does high homocysteine occur?
Cystathionine —> cysteine —> accumulation of cysteine —> inhibition of cystathione synthesis —> homocysteine accumulation —> release in the bloodstream
What can lead to the defect of neural tubes in the fetus? How can it be prevented?
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
Mutation in N5,N10 methylene-FH4 reductase can cause what?
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
What inhibits folate absorption?
Anticonvulsants
What is elevated in vitamin B12 deficiency and what is elevated in folate deficiency?
In B12 deficiency, both methylmalonic acid and homocysteine are elevated in serum while only homocysteine is elevated in folate
What cells produce intrinsic factor?
Gastric parietal cells
Explain THF trap. What can the deficiency of vitamin B12 lead to?
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
What can homocysteine be turned into?
It can be methylated to form methionine or condensed to form cystathionine
How is the risk of neural tube defects decreased?
The intake of folate supplement before conception, and at least 1 month after conception
