Betaine And Methyl Donor Metabolism

BingDing

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Hey all, I have been studying methyl donor metabolism and want to post a couple things.

The MTHFR thread has some related stuff and so does the choline thread.

This article Betaine in human nutrition has got a ton of information and cites 271 sources. The author works for a food products company and sort of sounds like the sugar beet lobby, but it seems to hang together.

Betaine works fine in the methylation cycle to lower homocysteine. It is also an osmolyte that protects cells from external osmotic stress, a lipotrope that prevents or reduces accumulation of fat in the liver, and was used in the 1950s to improve cardiac health in different groups of ill patients.

I can't refind it but one study used 15g/day for six months without any toxicity.
 

aguilaroja

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BingDing said:
...Hey all, I have been studying methyl donor metabolism...

Betaine works fine in the methylation cycle to lower homocysteine. It is also an osmolyte that prects cells from external osmotic stress, a lipotrope that prevents or reduces accumulation of fat in the liver, and was used in the 1950s to improve cardiac health in different groups of ill patient

http://raypeat.com/articles/articles/co2.shtml

"The effects of carbon dioxide on many biological processes involving methylation and acetylation of the genetic material suggest that the concentration of carbon dioxide during gestation might regulate the degree to which parental imprinting will persist in the developing fetus."

"prolonged decrease in carbon dioxide can increase the susceptibility of proteins to glycation (the addition of aldehydes, from polyunsaturated fat peroxidation or methylglyoxal from lactate metabolism, to amino groups), and a similar process is likely to contribute to the methylation of histones, a process that increases with aging. Histones regulate genetic activity."

"With aging, DNA methylation is increased (Bork, et al., 2009). I suggest that methylation stabilizes and protects cells when growth and regeneration aren't possible (and that it's likely to increase when CO2 isn't available). Hibernation (Morin and Storey, 2009) and sporulation (Ruiz-Herrera, 1994; Clancy, et al., 2002) appear to use methylation protectively.
Parental stress, prenatal stress, early life stress, and even stress in adulthood contribute to “imprinting of the genes,” partly through methylation of DNA and the histones.
"Methionine and choline are the main dietary sources of methyl donors. Restriction of methionine has many protective effects, including increased average (42%) and maximum (44%) longevity in rats (Richie, et al., 1994). Restriction of methyl donors causes demethylation of DNA (Epner, 2001). The age accelerating effect of methionine might be related to disturbing the methylation balance, inappropriately suppressing cellular activity. Besides its effect on the methyl pool, methionine inhibits thyroid function and damages mitochondria."

"In humans and other animals that are susceptible to cancer, one of the genes that is likely to be silenced by stress, aging, and methylation is p53, a tumor-suppressor gene."

"Several diseases and syndromes are now thought to involve abnormal methylation of genes. Prader-Willi sydrome, Angelman's syndrome, and various “autistic spectrum disorders,” as well as post-traumatic stress disorder and several kinds of cancer seem to involve excess methylation."
 
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BingDing

BingDing

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Thanks, aguilaroja. Can you conclude from those quotes that depleting the pool of methyl donors is desirable? RP's statements seem contradictory to me, methylation of DNA can be protective in some cases and cause disease in others.

DNA aside, methyl donors are required in the synthesis of CoQ-10 in the mitochondria, norepinephrin (and thus epinephrin), melatonin, methylcobalamin, creatine, phosphatidylcholine, and carnitine, and are allosteric effectors (increase the effects of) CBS, the rate limiting enzyme in the homocysteine -> cysteine pathway. (source cited here)

The CoQ-10 seems especially important since it is used in the electron transport chain in the production of ATP, as well as being an antioxidant. It seems highly unlikely that RP would advocate depleting methyl donors to the point that it inhibits oxidative respiration. I just wish he would explain this more.

It may be that RP is saying that very little dietary methionine is required since methyl donors are continuously recycled, which is plausible. That leaves the open question of what to do if the recycling is inefficient.

In the MTHFR thread iloveSugar asked RP if he could benefit from methylfolate and methylcobalamin. RP said "they often help, regardless of the mutation". I would suggest that supplementing betaine is consistent with that. And may have other benefits as that article asserts.
 

aguilaroja

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BingDing said:
DNA aside, methyl donors are required in the synthesis of CoQ-10 in the mitochondria, norepinephrin (and thus epinephrin), melatonin, methylcobalamin, creatine, phosphatidylcholine, and carnitine, and are allosteric effectors (increase the effects of) CBS, the rate limiting enzyme in the homocysteine -> cysteine pathway. (source cited here)

The CoQ-10 seems especially important since it is used in the electron transport chain in the production of ATP, as well as being an antioxidant. It seems highly unlikely that RP would advocate depleting methyl donors to the point that it inhibits oxidative respiration. I just wish he would explain this more....

In the MTHFR thread iloveSugar asked RP if he could benefit from methylfolate and methylcobalamin. RP said "they often help, regardless of the mutation". I would suggest that supplementing betaine is consistent with that. And may have other benefits as that article asserts.

I would welcome hearing/reading Dr. Peat's extended views about methylation. The methylation pathways above are ones I have read about previously. I would further welcome extended information from Dr. Peat about sulfur bio-molecules, Coenzyme Q, and more. I made earlier queries and am still reflecting on things. I recall in the past Dr. Peat has been concerned about contaminants in CoQ products. The citations suggest that some methylation actions may be less restorative responses when full generative mode is impaired.

I am not being modest nor intentionally evasive. I don't have a summary view of methylation. Methylation hype is going on 15 to 20 years now, in certain circles. Given how confused advocacy of, say, anti-oxidant or oxygenation therapies has been, I hold enthusiasm for methylation supplements in reserve. Methylcobalamin and, say, betaine (a close relative of glycine, which in turn has marked restorative properties) may be effective for more primary reasons than MTHFR mutations & methylation "deficit". Perhaps Dr. Peats specific thoughts can be further educed.

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http://www.ncbi.nlm.nih.gov/pmc/article ... -00159.pdf

Front Physiol. 2014 Apr 24;5:159. doi: 10.3389/fphys.2014.00159. eCollection 2014.
The betaine/GABA transporter and betaine: roles in brain, kidney, and liver.
Kempson SA1, Zhou Y2, Danbolt NC2.

"A summary of the multiple roles of betaine and BGT1 in the tissues discussed in this review.... Both are present in brain but their roles are least understood in this tissue. Betaine is of undoubted importance for liver metabolism, but the importance of BGT1 for betaine transport remains unclear even though its abundance in liver is almost 50-fold greater compared to the kidney. The best documented roles are in the kidney where betaine serves as one of several compatible osmolytes that are accumulated by cells in the renal medulla in order to adapt to the high extracellular osmolarity."

"Taking a broader view, a number of studies have reported a strong association between localized hypertonicity and inflammation (Hubert et al., 2004; Schwartz et al., 2009). The contribution of osmotic stress to the development and progression of chronic inflammatory diseases, such as arthritis and inflammatory bowel disease (IBD), is not well-understood. However, in the case of IBD, recent research suggests that episodes of local hyperosmotic stress can upregulate the release of pro-inflammatory cytokines by colorectal epithelial cells (Abolhassani et al., 2008; Schwartz et al., 2008). Future studies may reveal that therapeutics targeting localized hyperosmotic adaptation could represent a novel class of drugs for the treatment of many disorders. For example, inhibitors of aldose reductase have been shown to prevent inflammatory complications such as sepsis and asthma (Srivastava et al., 2005; Ramana, 2011)."
 
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Isn't trimethylglycine technically full of methyl groups?
 
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BingDing

BingDing

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A belated thanks for your response, aguilaroja, I appreciate you sharing your thoughts, as always.

My confidence in what I write at this level is moderate since I have so little background. I sure didn't set out two years ago to master biochemistry. But when I read the same thing several places I have to consider that it's accurate.

I'm trying to piece together the meaning of two different lab tests that had the same results, and low S-adenosyl methionine/SAMe corresponds with several of the other low results by the pathways mentioned.

Low alpha lipoic acid was another result on both tests, which is a required cofactor in ATP production. But SAMe is not used as a methyl donor but in a radical SAMe mechanism

Radical SAM is a designation for group of enzymatic reactions sharing the property that an iron-sulfur cluster in the enzyme cleaves S-Adenosyl methionine (SAM) reductively to produce a radical, usually a 5′-deoxyadenosyl radical, as a critical intermediate.[1] The radical intermediate allows enzymes to perform a wide variety of unusual chemical transformations.

The Wiki page on ALA says, in a long paragraph about biosynthesis full of words I don't know

Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase

and a google image search turns up a page on ALA with this diagram

My conclusion is that inhibiting ATP by these different mechanisms because of a little understood epigenetic risk is probably not smart. Hopefully keeping CO2 levels up will reduce the risk.

SS, yes, TMG transfers a methyl group to B12 which then transfers one to homocysteine to produce methionine again.
 

Nenupharlily

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So does trimethylglycine/TMG is something we want to avoid ? A detox specialist recommended it to me...o_O
 

ddjd

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DNA aside, methyl donors are required in the synthesis of CoQ-10 in the mitochondria, norepinephrin (and thus epinephrin), melatonin, methylcobalamin, creatine, phosphatidylcholine, and carnitine, and are allosteric effectors (increase the effects of) CBS, the rate limiting enzyme in the homocysteine -> cysteine pathway. (source cited here)
above this comment another user said ""Methionine and choline are the main dietary sources of methyl donors.". if choline is a methyl donor, is choline required to turn choline into phosphatidylcholine. I thought it was just methionine thats the methyl donor, not choline.
 

Razvan

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Just bumping this thread I found after reading @InChristAlone log. @Razvan would you mind saying what benefits you notice and what prompted you to start taking it?

Thanks!
Good stools , good digestion, increase in appetite ( since I'm a high histamine low body fat, low appetite person) and low cortisol and relaxation especially paired with taurine.
 

Osukhan

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Good stools , good digestion, increase in appetite ( since I'm a high histamine low body fat, low appetite person) and low cortisol and relaxation especially paired with taurine.
totally agree, i also have been using taurine and tmg regularly with similar benefits
 

Peater

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What sort of dose are people taking? I take 2x 1ml scoops (Not sure what that is in mg but I think it's just under half a teaspoon)
 

Osukhan

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What sort of dose are people taking? I take 2x 1ml scoops (Not sure what that is in mg but I think it's just under half a teaspoon)
usually take tmg preworkout 1.5 grams, and taurine 4-6g divided up through out the day (2 grams 2-3 times a day)
most preworkouts have tmg these days
the one i have been using off and on is Transparent Labs-Lean
 

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