Why do we need folate in our diet?
Although we can make pteridine rings, PABA and Glu, we don’t have the enzyme to put it all together.
How is folate converted to its active form?
2 reduction steps by dihydrofolate reductase and NADPH gives you tetrahydrofolate (FH4)
What parts of FH4 can bind methyl groups?
N5 and N10
At what point is the methyl group irreversible bound to FH4?
What is the main source of single carbon units for FH4?
Gluc -> -> Ser -> Ser adds to FH4 form N5,N10-methylene-FH4. Ser is responsible for maintaining the one carbon pool and is not readily depleted because it can be synthesized from glucose.
What are the main amino acids that contribute methyl groups to FH4?
Serine, glycine and histidine.
What does FH4 do with the methyl groups once it gets them?
Methyl group is transferred from FH4 in purine synthesis and synthesis of dTMP from dUMP.
How do methotrexate and 5-gluorouracil work?
Methotrexate competitively inhibits dihydrofolate reductase. This prevents reduction of FH2 back to FH4. You need FH4 to make dTMP for DNA synthesis, so it stops cell replication by stopping DNA synthesis. 5-fluorouracil directly blocks the conversion of dUMP to dTMP.
What is different about vitamin B12 in vitamin supplements?
The X-ligand that is normally bound to cobalt is cyanide. Cyanide makes it a stable complex. In the body, it is not bound to cyanide and can participate in many different reactions.
What reactions does B12 participate in?
Transfers a methyl group from homocysteine to form methionine. Moves the Acetyl CoA group on methylmalonyl CoA to form Succinyl CoA.
The methylation reactions carried out by folate are insufficient to carry out all methylation reactions in the body. What enzyme is responsible for carrying out most methylation reactions?
S-Adenosylmethioinine (SAM), note that it is highly involved in forming N-methyl groups.
How do you synthesize SAM?
After donating its methyl group, SAM converts to SAH which is then cleaved to form adenosine and homcysteine. B12 adds the methyl group that it received from N5-methyl-FH4 to homocysteine to form methionine. 3 phosphates are release from ATP when reacts with methionine to form SAM.
Why can’t you just supplement you diet with methionine to keep the one carbon pool running?
You would need so much of it it is nearly impossible to do. The one carbon pool really needs to be tied back to glucose to be sufficient.
What symptoms do you see first when people are folate deficient?
GI and Erythropoiesis. When you are folate deficient, the reaction shown below becomes rate limiting, which affects DNA synthesis, especially in cells dividing rapidly. Note that in erythropoiesis, if you don’t have enough precursor to form DNA, the cells arrest at the megaloblast stage, hence the name megaloblastic anemia.
What are the different chaperones that guide B12 through the digestive path?
1) R-binders in mouth 2) Intrinsic factor in small bowl and into blood stream
Why do elderly people often suffer from B12 deficiency?
Decreased parietal cells = decreased IF. Decreased pancreatic enzymes = decreased R-binder cleavage.
What are the consequences of B12 deficiency?
1) Methylmalonyl CoA: accumulates in cells, methylmalonic acid is released, diffuses into plasma and can be analyzed (MMA test for B12 deficiency) 2) Inhibition of Homocysteine -> Methionine causes all the folate to go to N5-methyl FH4 and accumulate, now there is not enough N5,N10 methylene FH4 to carry out dTMP synthesis and you get megaloblastic anemia.
Why shouldn’t you treat a patient with B12 deficiency with folate?
Although you take care of the megaloblastic anemia by continuing to allow for synthesis of dTMP, you are not acknowledging the irreversible diffuse neurological symptoms that come from reduced SAM synthesis.
Associated with anencephaly and spina bifida.
Folic acid deficiency
What other amino acid can be used as an indicator for B12 deficiency? What other deficiencies may it indicate?
Hyperhomocysteinemia. Homocysteine will build up if you are deficient in B6, B12 and/or folic acid.
Why is folic acid linked to cancer?
When there is not enough dTTP around, the cell will use dUMP instead. When dUMP is incorporated into a DNA strand, it overwhelms the repair pathway and allow for increased mutations. Also, if Us persist through replication and are include on the opposite strand, repair enzymes will cause a DS break in the DNA.
What are the 3 down sides to dietary folic acid supplementation?
Suppresses manifestations of B12 deficiency, may promote cancer cells and raises serum levels of folic acid