Jeff Huseby says, "How does the body buffer excess methyl groups if the glycine buffer
system is maximally suppressed by methylfolate and all methylation needs have been satisfied. If the
answer is it excretes them, then why does it need the glycine buffer system in the first place? Can
it just excrete them without it?" Well, it's cyclical. So,
okay, "how does the body buffer excess methyl groups if the glycine buffer system
is maximally suppressed by methylfolate?" You mostly have methylfolate in the fasting state
and you have MTHFR because this is how it works.
In the fed state, that's where you're going to get your methylfolate obviously
but a given molecule of methylfolate goes through the cycle of becoming methylated like 18,000
times a day. So you have one out of 18,000 methyl groups attached to the methylfolate that you ate.
And that methyl group is totally insignificant in the context of the total number of methyl
groups that that particular folate molecule will experience in one day. Furthermore, it,
yeah, it might help recycle homocysteine to methionine, but probably not because
all your new methionine comes in in the fed state. So not all your methylfolate comes in in the fed
state because you remethylate fully in the fasting state, but all your new methionine comes in in the
fed state. You don't get new methionine that is not recycled from homocysteine. You don't get
new coming in except during the fed state. And so during the fed state, your main source of
methyl groups is the methionine that came in in the protein that you ate. And so
that methionine increases SAM. That's why SAM is a fed state molecule.
That's not saying that there's no SAM in the fasted state. There is, but SAM goes up in
the fed state and down in the fasted state. And so when SAM goes up in the fed state,
that does a couple things, it shuts off MTHFR. So after a meal, you don't use MTHFR at all.
It also shuts down BHMT. I'm not sure if it shuts down choline dehydrogenase, but it might.
So you're not using choline and betaine to remethylate homocysteine during the fed
state. You are not recycling homocysteine therefore during the fed state. SAM also
increases CBS activitiy. So during the fed state,
you are diverting most of your methionine into homocysteine catabolism to cysteine.
Therefore, to taurine, sulfate, maybe glutathione, depending on how much you need to synthesize, et
cetera. So the flux is methionine from the meat or from whatever protein in your diet,
it goes through one methylation reaction, it becomes homocysteine. It then goes to
this transsulfuration pathway where it becomes cysteine and then goes on. That's the fed state.
Because MTHFR is shut off, then you're not going to have much methylfolate. Yeah, you ate some
methylfolate there, but you don't have much methylfolate there.
So methylfolate is not going to shut off the glycine buffer system. The glycine buffer
system will be active under these conditions. Because your SAMe levels are high and they're
higher than what you need for most of the methylation reactions.
So also during the fed state, you're going to be using the glycine buffer system a lot.
So in the fed state, the methionine engages in a methylation reaction.
That might be a methyltransferase for something that needs to be methylated. If you've exceeded
the need for that, which you probably have, then some of it's going to methylate glycine.
Then become homocysteine, then be catabolized to cysteine through the transsulfuration
pathway. That's the fed state dynamic. The fasting state dynamic is that you aren't
eating any protein, so you don't have any new methionine coming in, so your SAMe levels drop.
SAMe levels dropping, relieves the suppression of MTHFR and BHMT and
allows the recycling of homocysteine. SAMe levels dropping, essentially turns off the
transsulfuration pathway, or at least it lowers the volume on that pathway.
Because you now have lower SAMe, that's why you have more methylfolate because now MTHFR is
active. Because of that, methylfolate is seen as a signal of the fasting state, low SAMe dynamic.
Because of that, the glycine buffer system where glycine N-methyltransferase, GNMT, interprets
the methylfolate as that signal and says, "Methylfolate is here, that must mean SAMe levels
are low. That means I should go home and stop working." So the glycine buffer system turns off.
The answer is, you asked, "How does the body buffer excess methyl groups if the glycine buffer
system is maximally suppressed by methylfolate and methylation needs have been satisfied?" The body
doesn't buffer the excess methyl groups if the glycine buffer system is maximally suppressed.
When you have excess methyl groups, you don't have methylfolate to shut off the
glycine buffer system. So when you have excess methyl groups, that's when the glycine buffer
system turns on. When you don't have excess methyl groups, that's when it turns off.
"If the answer is it excretes them, then why do we need the...?" Well, yeah, it's not that it
excretes them. The glycine buffer system, it's not about excreting the methyl groups, it's
as an analogy to a chemical buffer. A chemical buffer is something that will...
A pH buffer, for example, it's something that will keep you in a certain range of pH and will prevent
you going from going one or extreme or the other. The glycine system is like a biochemical buffer.
So to a certain extent, those methyl groups can be salvaged in the mitochondria
during the fasting state, by taking them off of the methylated forms of glycine.
It's only if you exceed the capacity to cleave them off, that they do wind up in the urine.
They do wind up in the urine, so you generally do exceed to some extent, the capacity to
take those methyl groups. But the preference is to take them later, not to excrete them. The
excretion is always going to be there and it will increase if you really exceed the capacity of the
buffer system to salvage them. All right, thank you for your question, Jeff. Hope that helps.