One Carbon Metabolism Flashcards
What does folate look like in the diet?
It is polyglutamated. This means that we have one folate molecule with any number of glutamate molecules. So when it gets into the jejunum it has to be broken down into a mono glutamate before it can be reabsorbed.
Folate conjugase
Enzyme responsible for converting polyglutamated folate in monoglutamated folate so that it can be absorbed in the jejunum.
What does phynoitin do?
It inhibits folate conjugase
What affect do OCPs and alcohol have on folate?
They inhibit uptake into the jejunal epithelium.
How do we make folate into a useful form?
FOlate –> DHF –> THF
- the enzyme that does both of these rxns is called DHFR. Dihydrofolate reductase.
What is the mechanism of action of methotrexate and aminopterin?
They inhibit DHFR, so that THF can not be made from folate.
- It has a similar structure so Folate. The only difference is a nitro group instead of a hydroxyl group on folic acid.
What is methotrexate used for and why is it effective?
It is a chemotherapeutic. It doesn’t allow for THF to be made, so purine and thymidine synthesis will be halted and cells will begin to die.
What is Leucovorin and why is it effective?
It is usually given in conjunction with methotrexate because it blocks the metabolic blocks of methotrexate. This makes no sense, why would we want this? - because it is specific towards less polyglutamated cells (normal cells), whereas methotrexate is more specific towards more polyglutamated cells (cancer cells).
- It bypasses DHFR, it can get into the cells and be converted into THF by other means other than with DHFR.
How do bacteria make THF?
They do not need to get folate from the diet, but rather can synthesize folate from a precursor called PABA. From there it is the same as in humans.
Sulfonamide
An enzyme that selectively inhibits DHPS, which is the enzyme responsible for converting PABA into folic acid. Therefore no THF will be made.
- doesn’t allow bacterial DNA to be made.
Trimethoprim
Inhibits bacterial DHFR and thus does not allow bacteria to synthesize DNA.
N10 formyl THF
Comes from the addition of formate to THF.
- it is used as a carbon donor in purine synthesis
N5N10-methylene THF
Comes from the addition of either glycine, serine, or formaldehyde to THF
- used as a carbon donor in thymidine synthesis
How does SAM get made?
From methionine
- the enzyme SAM synthetase does this reaction
What happens once SAM is made?
It is involved in DNA methylation as well as epinephrine synthesis. It is then converted into S-adenosyl homocysteine and eventually to homocysteine.
Homocysteine
- Marker for cardiovascular disease.
- levels are inversely related to B6, B12 and folate
What are always in which we can get rid of homocysteine? Explain why it’s levels are inversely proportional to B6, B12, and folate
- Homocysteine can be converted into cystein via B6. If you are low in B6 then you will be high in homocysteine.
- you can also convert homocysteine into methionine, which uses B12 as a precursor. This reaction then converted 5-methyl-tetrafolate into THF. So, if you are low in B12, all of your folate will be stuck in the form of 5-methyl-tetrafolate.
Why does the folate trap affect both THF and SAM?
- THF because it won’t be converted if you are low in Vitamin B12
- SAM because you need methionine to make SAM.
What are the Two methyl group Donors and what processes are they largely responsible for?
THF - Purine synthesis and thymidine synthesis
SAM - epinephrine synthesis and DNA methylation
B12 deficiency bio markers
Elevated homocysteine
Elevated methylmalonyl CoA
Consequences of b12 deficiency
Macrocytic anemia
Peripheral neuropathy - ataxia, dementia
Smooth sore tongue
Consequences of folate deficiency
Same as B12 deficiency except no neurological problems because methionine will still be Made and thus SAM will be made.
- macrocytic anemia
What are the cut offs for MCV?
Greater than 100 is considered macrocytic
Less than 80 is microcytic
