Glutathione

[humptydumpty]

Hi Everyone, I don't have CFS, but got attracted to this forum by high quality posts. I would to learn more about glutathione, how it is produced and recycled.

A few months ago I ran a spectracell micronutrient tests which told me I am desperately low in antioxidant function. I was supposed to supplement NAC among others, but I actually started with reduced glutathione with good results, some health problems resolved. After learning that glutathione is actually hydrolized to the three constituent amino acids on digestion, and getting additional glutamate might a be a bad idea, I switched to NAC. I also saw someone saying to supplement glutamine and glycine and rely on homocysteine for cysteine. I have elevated homocysteine so that rings true. Where can I learn more about this?

I would also like to find out why would glutathione be low with high homocysteine at the same time and CBS upregulation (lack of some substrates/co-factors?).

 

[Valentijn]

I would also like to find out why would glutathione be low with high homocysteine at the same time and CBS upregulation (lack of some substrates/co-factors?).

The CBS gene is responsible for converting homocysteine back into cysteine, which then hooks up to form glutathione. If the gene were downregulated, homocysteine could be high and glutathione low. Additionally, insufficient B12 or methylfolate also might be slowing things down.

B6 supplementation would help in converting homocysteine into cysteine, and B12 and/or methylfolate might help in keeping things moving and lowering homocysteine.

 

[humptydumpty]

Assuming high homocysteine, why would insufficient b12 or methylfolate be slowing things down for glutathione synthesis?

Does anyone have a link with the glutathione pathways well modeled. Like what are the enzymes regulations and substrates? Maybe that is not well understood yet though.

 

[Valentijn]

Assuming high homocysteine, why would insufficient b12 or methylfolate be slowing things down for glutathione synthesis?

Does anyone have a link with the glutathione pathways well modeled. Like what are the enzymes regulations and substrates? Maybe that is not well understood yet though.

Reactions in the methylation cycle generally can run in two directions. There might be a problem with things running a bit in the wrong direction, and supplementing might help with that.

If you look for "methylation" at google images, you should be able to find something showing both methylation and the pathway from homocysteine into cysteine and maybe all the way to glutathione.

 

[humptydumpty]

Reactions in the methylation cycle generally can run in two directions. There might be a problem with things running a bit in the wrong direction, and supplementing might help with that.

I understand that some reactions can flow both directions, but I don't understand how does that answer my question. Can you be more specific?

 

[Valentijn]

I understand that some reactions can flow both directions, but I don't understand how does that answer my question. Can you be more specific?

Sorry, no. It's not an area I've really looked into.

 

[PeterPositive]

Assuming high homocysteine, why would insufficient b12 or methylfolate be slowing things down for glutathione synthesis?

I think the main problem is that with insufficient B12 and folate the cycle either slows down or gets stuck and it's no longer driving the glutathione production (and SAMe) at the end of the chain.

B12 and folate are necessary to re-methylate homocysteine and keep the "wheel turning", if it slows down too much the trans-sulfuration pathway will also be affected.

I think Rich Von Konynenburg explained this pretty well in this article:

10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with CFS.

11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much, are oxidized to form cystine, pass through hydrogen sulfide, and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine rather than cystine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.