BHMT, Transsulfuration, and Methionine Synthase Pathway

[Lotus97]

I have several questions about this, but I want start with something Genetic Genie told me. They said I had to stimulate the BHMT pathway because I have 3 homozygous BHMT polymorphisms

DMG and the supplement TMG also stimulate the BHMT pathway to convert homocysteine to methionine, but one should take caution if they are sensitive to methyl donors.

Does DMG (not to be confused with TMG) stimulate the BHMT pathway? Because what Rich said about DMG and the BHMT pathway makes it sound like it does the opposite. Am I missing something?

A little TMG is often helpful when methylfolate and B12 supplementation are started, because it can help to raise SAMe, needed for recycling methyl B12. After these supplements are well underway and methionine synthase is coming up in activity, the TMG can be stopped, or DMG can be added to counter the BHMT pathway, so as to route more of the homocysteine to the methionine synthase pathway and the transsulfuration pathway.

Betaine and TMG are the same substance. Betaine HCl has a hydrochloric acid molecule bound to it. Yes, if you take betaine HCl, you will also have the benefit of TMG. However, note that TMG stimulates the alternative BHMT pathway from homocysteine to methionine in the liver and kidneys. TMG will promote production of SAMe, but it can shunt flow away from the methionine synthase enzyme, which is partially blocked in ME/CFS. It's important to get this enzyme going, because it is linked to the folate metabolism, which is needed to make new DNA and RNA, and also because it regulates the entire sulfur metabolism. In Amy Yasko's protocol, she recommends starting with some TMG, and then after the B12 and folate have been built up some, to add DMG, which will inhibit the BHMT reaction by product inhibition, and that will push more of the homocysteine through the methionine synthase reaction.

Best regards,

Rich

 

[triffid113]

I aso have 3 BHMT mutations. I believe that TMG is important for health for EVERYONE. The people who get the most betaine by DIET get 2g/day and I try to take that. From my experimentation, I do not believe you can force a pathway. It goes at the speed it goes. You can stop a pathway with improper nutrition (or improper for you), but cannot speed it up. The B12+folate pathway is INHERENTLY slower than the BHMT pathway because it requires more chemical reactions to occur on that pathway. The BHMT pathway is intended to bee the shuttlecock that keeps the boiler from bursting under pressure...if you do not assist that pathway your homocysteine will soar. And sure, you'll have plenty of fuel for the B12+folate pathway, but it will not work faster, and the homocysteie will kill you over time. The key is IMHO to supply the BHMT pathway and never have more than 6.3 of homocysteine sitting in the queue waiting to be converted back to methionine. That s ENOUGH of a queue. Any more is not gonna help you. And homocysteine is real easy to measure.

As for DMG...I have no interest in it. I don't believe it serves any purpose. TMG works, why muck with anything less?

 

[Lynn_M]

Lotus97,
I have puzzled over this myself. I don't think DMG stimulates the BHMT pathway. I think taking it as a supplement would create back pressure and encourage the long pathway via methionine synthase.

 

[Lotus97]

I aso have 3 BHMT mutations. I believe that TMG is important for health for EVERYONE. The people who get the most betaine by DIET get 2g/day and I try to take that. From my experimentation, I do not believe you can force a pathway. It goes at the speed it goes. You can stop a pathway with improper nutrition (or improper for you), but cannot speed it up. The B12+folate pathway is INHERENTLY slower than the BHMT pathway because it requires more chemical reactions to occur on that pathway. The BHMT pathway is intended to bee the shuttlecock that keeps the boiler from bursting under pressure...if you do not assist that pathway your homocysteine will soar. And sure, you'll have plenty of fuel for the B12+folate pathway, but it will not work faster, and the homocysteie will kill you over time. The key is IMHO to supply the BHMT pathway and never have more than 6.3 of homocysteine sitting in the queue waiting to be converted back to methionine. That s ENOUGH of a queue. Any more is not gonna help you. And homocysteine is real easy to measure.

As for DMG...I have no interest in it. I don't believe it serves any purpose. TMG works, why muck with anything less?

I don't know how you can possibly make a blanket statement like "EVERYONE needs TMG". Not everyone needs additional methyl donors. There's a study that shows that for some people even just hydroxocobalamin and a little bit of methylfolate increases SAMe and donates enough methyl groups to get methylation going.
http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf
Some people do need methylcobalamin and higher doses of methylfolate and *SOME* people might need additional methyl donors like TMG and SAMe, but certainly not everyone or even a large percentage of people.

There's no way anyone is getting anywhere near 2000 mg of betaine/TMG from their diet unless they're eating a serving each of quinoa, wheat bran, spinach, and beets everyday (four total servings).
http://en.wikipedia.org/wiki/Trimethylglycine
I can't imagine why many people would need anywhere near that much.

I'm also not sure where you're getting your information about BHMT and homocysteine. Is there a study about this? It's only very recently that there's even been a study with SAMe and homocysteine (let alone methylation and homocysteine).
http://www.ncbi.nlm.nih.gov/pubmed/19422296?dopt=Abstract

Dietary supplement S-adenosyl-L-methionine (AdoMet) effects on plasma homocysteine levels in healthy human subjects: a double-blind, placebo-controlled, randomized clinical trial.
OBJECTIVES: To determine if exogenous S-adenosyl-l-methionine (AdoMet), a commonly used nutritional supplement, increases the level of plasma homocysteine (Hcy), a potential cardiovascular risk factor, in healthy human subjects.
DESIGN: Double-blind, placebo-controlled, randomized clinical trial.
SETTING: Mayo Clinic, Rochester, Minnesota.
SUBJECTS: Fifty-two (52) healthy human volunteers.
INTERVENTION: Subjects received placebo or AdoMet (800 mg per day) for 4 weeks. Hcy levels were measured before and after administration of AdoMet or placebo.
OUTCOME MEASURES: The primary outcome measure was change in Hcy level. Secondary outcome measures included an interim Hcy determination (at 2 weeks) and changes in levels of high-sensitivity C-reactive protein (hsCRP), lipids, and alanine aminotransferase.
RESULTS: There was no statistically significant change in Hcy between groups. Similarly, no statistically significant differences in change in Hcy or hsCRP levels were observed at 2 or 4 weeks. There was a small but statistically significant increase (p < 0.04) in alanine aminotransferase at week 2 and a statistically significant decrease (p < 0.04) in total cholesterol in the AdoMet group compared with the placebo group.
CONCLUSIONS: AdoMet at a daily dose of 800 mg for 4 weeks does not appear to significantly affect Hcy levels in the blood.

 

[nkm]

My communication with Rich and Prof. Richard Lord (Chief Science Officer at Metametrix) both confirmed DMG is an inhibitor to the BHMT pathway. I know Yasko actively uses this pathway in her protocol whereby she first stimulates it with TMG to increase SAMe levels and then uses DMG to inhibit BHMT while working on the long route with folate/B12.

I respect a lot of what Dr. Yasko does but at the same time, to suggest taking 400mg of a PS/PE/PC combination is going to give improvements by short cutting the methylation cycle doesn't sit well with me. Firstly, it makes little sense to think a small amount of phospholipids is going to be sufficient for the BHMT pathway. Secondly, the BHMT pathway is mainly in the liver and [IIRC] kidneys and not so much the CNS.

It would make more sense to say autistic kids get a benefit from this combo because the neurons and their mitochondria are getting the material to repair their membranes. This would be backed up with all the research into why omega 3 [fish oil] works wonders for kids that are ADD/ADHD. In most cases I read about, the kids were off ritalin etc within a 3 months period of fish oil supplementation.

 

[Lynn_M]

nkm said "Secondly, the BHMT pathway is mainly in the liver and [IIRC] kidneys and not so much the CNS."

In his very recent subscriber webinair about folate, Dr. Ben Lynch said the BHMT pathway is in the liver, kidneys, and eyes, and that's it.

 

[Lotus97]

It seems there is a study where taking TMG lowered homocysteine
http://ajcn.nutrition.org/content/76/5/961.long
But how do you know it isn't just methylation that's reducing homocysteine? In which case TMG is optional. It is strange that TMG lowered homocysteine, but not SAMe unless there's something in both of these studies that I'm missing.

 

[Lotus97]

So dbkita also said that DMG inhibits BHMT. I don't think there was much of a question when I started this thread, but I wanted to clear it up due to what Genetic Genie said. He also talks about the role of BHMT and CBS. Also, dbkita has said that stimulating the BHMT pathway too much can cause a greater amount of dopamine to be converted into norepinephrine.

DMG inhibits BHMT which means more homocysteine for CBS means more ammonia, sulfites and sulfates. There is no absolute. Yes too much BHMT could stifle some of the main thoroughfare. But setting an absolute amount is not possible since it depends on the person's health status and genes. I think the NE increase from overstimulation is a stricter earlier constraint than lowering the methionine synthase activity. But if you are CBS +/+ and have BHMT issues I think you have to do something. Increased methionine synthase activity will simply drain down the trans-sulfuration pathway. Making you worse off. So there is a balance.

He is speaking here with someone who has both CBS and BHMT mutations.

You do have as cbs upregulation and several heterozygotes in bhmt. So some bhmt stimulation is needed to prevent overflow down the transsulfuration pathway. But it may be question of amounts. Usibg dmg with a cbs mutation would seem ill advised. But overstimulation will ramp ne relative to da so be careful. P5p / b6 can really up the cbs flow so watch out for that also. Betaine is betaine. So tmg is in both your tmg supplement and your betaine hcl. About 80% of your betaine hcl is tmg.

 

[Bluebell]

I have several questions about this, but I want start with something Genetic Genie told me. They said I had to stimulate the BHMT pathway because I have 3 homozygous BHMT polymorphisms. Does DMG (not to be confused with TMG) stimulate the BHMT pathway? Because what Rich said about DMG and the BHMT pathway makes it sound like it does the opposite. Am I missing something?

You can ask the person who runs GeneticGenie what his reasons are for stating that - he's a member here.

 

[taroki]

bump ....

Would DMG help get rid of the anxiety in someone who is +/+ for all 3 of BHMT-02, BHMT-04, BHMT-08? What else can help?

My boyfriend started having a lot of anxiety after doing Methyl B12 and Methyl Folate. Phosphatidyl Serine and TMG doesn't do anything for him.

I have just ordered a lot of supplements from Dr. Yasko to support Step One (for myself and him). Hopefully something will help with his anxiety.

 

[ahmo]

@taroki This is just a speculation. I really can only speak from my own experience. It doesn't seem to me that DMG would help w/ this, if bf

started having a lot of anxiety after doing Methyl B12 and Methyl Folate.

DMG, like TMG, is a methyl donor, so, it seems to me, this would only exacerbate the problem. Is he taking K+? Increasing folate can create need for K+, w/ breathlessness, anxiety type symptoms. May also possibly be due to increase in histamines &/or ammonia. I'm taking a lot of things to deal w/ these. Histamine: royal jelly, rutin, mangosteen; before I replace it w/ mangosteen, I also used quercetin. Sulfur/ammonia: ornithine, lysine, citrulline, butyrate. I started w/ yucca tincture, but it tasted so bad, I happily switched to ornithine when I discovered it. Good luck w/ finding the underlying cause.

 

[taroki]

What is K+? Is that potassium? I think he is ok on potassium since he eats a lot of bananas (and hair test shows potassium level is good).

hmm ... I noticed my histamine allergies, sulphite/sulphur sensitivites, and sometimes ammonia symptoms (suicidal thoughts, fibromyalgia) all increase after B12 and methyl folate. Oh well, hopefully things will be better after doing methylation properly with step one supplements.

 

[ahmo]

Yes, K+ = potassium. re your hmmm, yes, that's the reason to Start Low, Go Slow!

 

[taroki]

@ahmo
Did you say butyrate helped you with sulfur/ammonia issue? I bought some BodyBio sodium butyrate a while back but never got around to trying it. I did try Miyarisan (clostridium butyricum) from Japan and it is helping with food sensitivities/leaky gut.

I would love to get rid of the sulphite/sulphur issue but I don't think I'm ready to take more molybdenum yet until I am done with Dr. Yasko's step one supplements. I do know fecal transplant/poop pills will help but that would be a bit later.

 

[ebethc]

@ahmo - did the butyrate help w sulfur/ammonia issues?

thanks

 

[ahmo]

@ebethc Yes, the butyrate helps. And my body always wants it after I've done coffee enemas, presumably releasing ammonia.

 

[vortex]

bump ....

Would DMG help get rid of the anxiety in someone who is +/+ for all 3 of BHMT-02, BHMT-04, BHMT-08? What else can help?

My boyfriend started having a lot of anxiety after doing Methyl B12 and Methyl Folate. Phosphatidyl Serine and TMG doesn't do anything for him.

I have just ordered a lot of supplements from Dr. Yasko to support Step One (for myself and him). Hopefully something will help with his anxiety.

Did the DMG help with the anxiety?