Folate Metabolism Flashcards
What are the sources of Folate? What process takes out the folate form these food sources?
Green leafy vegetables
Cooking
What is the usual form of folate? What is the functional form of folate in the body?
Polyglutamates
Tetrahydrofolate is the functional form
What are the two major chemical pathways in the body that require THF?
Convert methylmalonyl-CoA to succinyl-CoA
Homocysteine to Methionine
What is the enzyme that converts folate to THF? Why is this an important drug target? What is the drug that inhibits it?
Dihydrofolate reductase
Methotrexate can inhibit production of THF, limiting cell growth
What is the function of THF? What is the most reduced form, and what is the most oxidized form?
Methyl carrier
Reduced = N5
Oxidized = N10
What is the reaction that is the major source of one carbon groups?
S +THF = G + (N5, N10-THF)
THF is found in foods mostly in a polyglutamate form, but it is found in the circulation in a monoglutamate form. What is the mechanism behind this?
Enterocytes hydrolyze poly to mono, then transport into circulation
How is THF absorbed by cells in the body?
Receptors take in N5-methyl-THF, then converted to polyglutamate form
What is the most abundant form of THF in the circulation? Inside cells?
N5-THF = circulation
Polyglutamase in the cells
Why is THF polyglutaminated once inside the cell?
Helps keep the molecule within the cell
What is the only reaction in the body that can convert N5-methyl-THF to THF? What is/are the vitamin(s) that is/are needed for this reaction to take place?
Methionine synthesis
B12 needed
What is the THF form used, and what is the form that is produced for: the S to G reaction?
THF to N5, N10
What is the THF form used, and what is the form that is produced for: methionine synthesis
N5 THF to THF
What is the THF form used, and what is the form that is produced for:thymidylate synthesis?
N5, N10 to Dihydrofolate
What is the THF form used, and what is the form that is produced for: purine synthesis?
N10-formyl THF to THF
What is the THF form used, and what is the form that is produced for: histidine catabolism?
THF to N5-formino THF
What does thymidylate synthease do? Why is this important?
Converts dUMP to dTMP
Essential for DNA synthesis
What is the ultimate source of all B12?
Bacteria
Do plants supply B12?
No, unless they have the bacteria that produce it
What are the metabolically active forms of B12?
Adenosylcobalamin
Methylcobalamin
What are the proteins in the stomach that bind free B12? What happens to the B12/protein complex when it enters the duodenum?
R proteins, which are degraded by pancreatic proteases, and intrinsic factor binds B12
What cells in the stomach produce intrinsic factor?
Parietal cells
Where is B12/intrinsic factor complex absorbed?
In the Ileum
What is the transport protein for B12?
Transcobalamin (haptocorin)
What is the cause of pernicious anemia (if not a dietary cause)?
Autoimmune attack against acid and pepsin secreting portion of the gastric mucosa
B12 can be taken up in the absence of intrinsic factor. How?
Large quantities force it into cells
What cells in the body form transcobalamin?
Ileal mucosa
What are haptocorrins?
Proteins in the circulation that bind B12, and allow for hepatocytes to take up B12
What happens to haptocorrins when they enter the liver?
Broken down, with B12 secreted into bile salts, to repeat the same process
What happens in part 1 of the Schilling test? Failing this part of the test indicates what?
- Oral load of radioactive B12
- Inject non-radioactive B12
- Screen urine for B12. Normal >7%
Failure = inability to absorb B12
What happens in part 2 of the Schilling test?
- Radioactive B12 administered orally w/ intrinsic factor
- IM injection of non-radioactive B12
Abnormal part 1 of the schilling test, but a normal part 2, indicates what?
Intrinsic factor deficiency
If both parts of the schilling test are abnormal, what does this indicate?
defective B12 absorption d/t other causes besides intrinsic factor deficiency
Adenosylcobalamin is need for what reaction?
Converting L-methylmalonyl-CoA to succinyl-CoA
What are the steps of taking AAs to succinyl CoA? (draw the pathway if needed)
AA (carboxylase) D-methylmalonyl-CoA (racemase) L-methylmalonyl CoA (mutase) Succinyl CoA
Which 5 amino acids can be converted into Succinyl-CoA?
Threonine
Methionine
Valine
Isoleucine
A lack of adenosyl cobalamin will result in the accumulation of what metabolite in the blood/urine?
L-Methylmalonyl CoA
What is the reaction that requires methylcobalamin?
Homocystiene to methionine +THF
What is the folate trap?
since N5 THF is the most common type, but THF is needed, and B12 needed to do the conversion, a lack of B12 will result in the useless N5THF only.
What causes the demyelination seen with a B12 deficiency?
failure of methionine synthase reaction, and lack of SAM
Why is it, that if you lack B12, you also have a functional folate deficiency?
THF is stuck in the N5-THF form, since the methionine reaction cannot take place
How does megaloblastic anemia result from the loss of THF?
Purine synthesis is halted in the thymidylate synthase reaction
Thymidylate synthase converts what to what? What vitamine is needed?
dUMP to dTMP
N5, N10-methylene-THF
What is the parasite that loves B12? What animal does this parasite come from?
Diphyllobothrium latum
Fish tapeworm
What is the anasthetic that destroys methylcobalamin?
NO2
What is the drug type that should be supplemented with B12?
PPIs
