6/10 - THF, B12, SAM Flashcards
What the hell is a carbon pool?
When we say carbon pool, we are referring to the group of molecules that act as transporters to move around single carbon units. For our purposes that is usually serine, and we are adding in this case to Tetrahydrofolate, FH4.
FH4 with his new Carbon friend then gets dumped onto a new product, like B12 or another serine or dTMP, etc, and in the process can be oxidized or reduced as needed.
Discuss the purpose and steps of Folate reduction
Folate is a simple molecule found in leafy green vegetables that is inactive. We can’t make this Pteridine ring - PABA - Glutamate strcture in the body, so we need this in our diet.
The glutamate is just a long molecule used to put the folic acid in the right places in the body.
We reduce Folate to dihydrofolate and then tetrahydrofolate, both in the same way, by using dihydrofolate reductase (DHFR) and turning NADPH to NADP+ in the process both times.
TH4 is our active form.
Why is it so important to remember that serine is the predominant methyl donor to THF?
Because we can generate Serine from Glucose! Super easy and helpful.
Where does Serine usually attack TH4 first and what does this help us with?
Serine typically will add to TH4 at its 5 and 10 position to make N5 N10 methylene-FH4, which can be turned into any other version of folate needed!
Outline the process of turning Glucose to Serine
- Via glycolysis, we turn glucose to 3-Phosphoglycerate
- As usual, we just add names to the compound to make an enzyme. We use 3-PG dehydrogenase to make 3-phospho-hydroxypyruvate (we are dehydrating, so we take that H off and put it on NAD+ in the process to make NADH)
- Then PLP with the help of glutamate (which becomes alpha ketoglutarate) turns our 3-PHP to 3-phospho-L-Serine, which turns to serine with the help of phosphoserine phosphatase (not a typo).
Serine has the hydroxy-methyl group that can then attach TH4
One important pharm point is the mechanisms. There are only a few, but one of the ones not explained in pharm was the effect of Methotrexate and 5-Fluorouracil on the methylation properties of TH4.
Outline this mechanism.
Basically, we need to turn dUMP to dTMP. So we need a methyl group added.
FH2 becomes FH4 via DHFR as discussed earlier, using up an H from NADPH, generating NADP+. (Methotrexate stops this)
FH4 then gets a carbon from Serine (the almighty carbon donor, turning it to Glycine), and becomes our all powerful N5 N10 Methylene FH4, the one that can turn into any folate.
This guy hits up dUMP to make dTMP (this is stopped by 5-Fluorouracil)
What happens when glycine transfers a 1-carbon unit to FH4?
NH4+ and CO2 are produced.
So serine and glycine both can help produce N5 N10-methylene-FH4.
What other groups can transfer carbons to FH4 and what do they produce?
Histidine is degraded to FIGLU, which reacts with FH4 to release NH4+, making glutamate, to produce N5 N10 methenyl FH4
Formate, derived from tryptophan, produces N10-formyl-FH4.
So we’ve talked about how to give FH4 a bunch of carbons. What do we do with them?
- Purine precursors get carbons 2 and 8 from FH4
- dUMP to dTMP (already discussed), which leads to the formation of Thymine
- Glycine can use an FH4 carbon to turn back to Serine
- B12 takes a methyl from 5-methyl-FH4 and puts it on homocysteine to make methionine (only fate of 5-methyl-FH4)
If we are folate deficient, that means we can’t make thymine, so no DNA. What does this cause?
Normal cell proliferation can’t happen, so megaloblasts develop.
B12 deficiency leads to what?
This guy accepts methyls from 5-methyl-FH4, which as discussed earlier, can’t be turned into anything else, so it accumulates, secondarily causing a folate deficiency.
Also, B12 turns MMCoA to Succinyl CoA, so without it, folks start peeing out their MMCoA and they start having neurological issues because of demyelination, which understandably can’t be alleviated by adding more folate.
A rise in MMCoA, typically due to B12 deficiency, causes what else to rise, and thus what else to happen?
Leads to accumulation of the MMCoA precursor, propionyl CoA, leading to the formation of methylcitrate since it will start replacing the normal acetyl CoA in citrate synthetase reaction.
This guy is a direct inhibitor of the TCA cycle, causing ketosis and hypoglycemia.
Vitamin B12 contains this metal
Cobalt, in a corrin ring that resembles a porphyrin
How is B12 involved in generating Succinyl CoA
B12 is the cofactor for MM-CoA Mutase, which catalyzes the re-arrangement of MMCoA to succinyl CoA.
It can also generate succinyl CoA from Valine, isoleucine, threonine, methionine, thymine, and propionyl CoA formed by the oxidation of fatty acids with an odd number of carbons.
What is SAM made from?
Methionine and ATP
