Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways

[alicec]

I honestly have no idea, I was hoping someone else would know.

The terms are used interchangeably. In solution, which is where all this biochemistry is going on, acids dissociate into their constituent parts, an anion and a hydrogen ion (well strictly speaking it is water plus a hydrogen ion - a hydroxonium ion - but this is always simplified to hydrogen ion). It is the anion - ie lactate, pyruvate - that gives specificity and this is what is measured.

There is another layer of complexity to this which is of relevance if you are trying to understand the details of the chemical equations. Most organic acids are so called weak acids, ie they only partially dissociate, in contrast to most inorganic acids, strong acids, which dissociate completely. The extent of dissociation is a property of the particular acid and is unchanging.

We don't need to worry about that, just focus on the anion which will tell you what you need to know about that particular metabolic step.

 

[Snow Leopard]

I can't believe I didn't see this thread until now.

I had been reading several earlier papers from this team:

"NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome."
http://www.ncbi.nlm.nih.gov/pubmed/22728138
http://www.researchgate.net/profile...e_syndrome/links/00b7d523bc15a7fe4c000000.pdf

Chapter five on a book about metabolism in disease:
http://www.ncbi.nlm.nih.gov/pubmed/25344988
http://www.researchgate.net/profile/Ying_Yong_Zhao/publication/268150873_Metabolomics_in_dyslipidemia_1/links/5464f00c0cf2052b509f28a9.pdf

The findings of this study also suggest reasons for why many of us do not tolerate alcohol for example.

One warning though, I noted some discussion about 'keto' diets and I'm not so sure this is wise.

A reduction of Acetyl CoA could be also due to other issues with fatty acid metabolism and if so, such diets would not be any more helpful. There are already some papers showing issues with fatty acid metabolism.

See: "Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitine palmitoyltransferase-I activity." http://www.ncbi.nlm.nih.gov/pubmed/21205027

And:
"Acylcarnitine Deficiency in Chronic Fatigue Syndrome"
http://www.ncbi.nlm.nih.gov/pubmed/8148455
http://www.ncbi.nlm.nih.gov/pubmed/9854142

lastly, I have some issues with the study, since there was no attempt to control for other factors such as diet and supplements (eg omega 3 oils, acetyl-l-carnitine vitamin Bs etc) that may account for the observed differences.

 

[alicec]

I too have been puzzling over some of these proposals about energy metabolism. I decided to look at various recent tests to see how my own results compare.

There could be evidence of faulty glycolysis, certainly urinary pyruvate is very low and I have on several occasions over the past few years had a high normal fasting blood glucose, though not always.

There is some evidence that other energy pathways are trying to compensate, particularly amino acids, including glutamate, feeding the Krebs cycle. I have no evidence of a glutamate to aspartate conversion - aspartate is quite low.

Urine creatinine is not elevated but I have polyuria. I have often wondered why it was as high as it was, given the dilution of the urine. I will be most interested to see what it is next OAT test, now that my polyuria has dramatically improved. I do have very low glycine which could be being used up in trying to make in trying to make creatine. Creatine supplements do seem to be helpful and I have plenty of muscle fatigue. So yes this might hold together.

The suggestion that the Kreb's cycle is more or less intact doesn't apply to me. Mine is definitely blocked at aconitase, as suggested above http://forums.phoenixrising.me/inde...tive-stress-pathways.37861/page-2#post-602784. It is even more badly blocked at succinate which is simply accumulating because it can't feed in to the electron transport chain and can't proceed around the cycle because everything is backing up behind aconitase.

Actually several of Rich's points in that post resonate with me. I have been eating a fairly low carb paleo diet for several years but increased my carb intake (still only moderate) to better feed my microbiota. It does seem to have done that (see http://forums.phoenixrising.me/inde...e-been-looking-for.26976/page-165#post-601104) but I have put on weight and have been wondering if I sometimes have reactive hypoglycaemia again, something that disappeared when I cut right back on carbs.

Rich's solution of restoring glutathione by lifting the methylation block doesn't resonate with me, however. After assiduous supplementation I now have much better methylation, glutathione and other oxidative stress markers, but all my energy pathways are just as badly stuffed.

Many of the parameters measured in the study were not in my blood and urine tests so it is hard to come to definite conclusions. Based on what I do have it seems mixed.

Still the study has raised important questions, particularly about glycolysis. Thanks so much @JaimeS for bringing it to the forum and for all your hard work in interpreting it.

 

[alicec]

then they DO go into the oxalate cycle...

They point out that blood glutamate is positively correlated with arginine and negatively correlated with glucose in the ME/CFS group, again implying a compensatory mechanism for impaired glycolysis, this time through the transformation of oxaloacetate to aspartate using aspartate trasaminase, when glutamate is deaminated to 2-oxoglutarate.

Not the same thing. @Gondwanaland was referring to oxalate, not oxaloacetate and other ketoacids. We are having an interesting discussion about oxalates on another thread http://forums.phoenixrising.me/index.php?threads/oxalate-dumping-a-probiotic-solution.37927/ and while it is tangential to this discussion it is interesting that the metabolic pathways blocked by oxalate are very relevant to what is being discussed here - viz B6 dependant transaminases necessary for amino and keto acid interconversion and biotin dependant carboxylases. Both are central to energy pathways.

 

[Sidereal]

Not the same thing. @Gondwanaland was referring to oxalate, not oxaloacetate and other ketoacids.

Actually, I do wonder what sorts of symptoms accumulation of oxaloacetate et al could cause. Perhaps what we call "oxalate issues" is in part this stuff.

 

[South]

I have been eating a fairly low carb paleo diet for several years but increased my carb intake (still only moderate) to better feed my microbiota

Could an answer to the diet dilemmas in this thread be a low-carb diet but add resistant starch? Resistant starch is not digested by the human gut, but IS digested by the microbiota. Especially the kind of resistant starch called RS2. It doesn't raise blood sugar, and I believe therefore doesn't ruin a low-carb diet. But the gut bugs would be much happier with it included in the diet.

Read Ripley's very first post in this thread, the section where he talks about RS2: and the links there may be good too:

http://forums.phoenixrising.me/inde...ge-is-it-the-key-weve-been-looking-for.26976/

 

[JaimeS]

Not the same thing. @Gondwanaland was referring to oxalate, not oxaloacetate and other ketoacids. We are having an interesting discussion about oxalates on another thread http://forums.phoenixrising.me/index.php?threads/oxalate-dumping-a-probiotic-solution.37927/ and while it is tangential to this discussion it is interesting that the metabolic pathways blocked by oxalate are very relevant to what is being discussed here - viz B6 dependant transaminases necessary for amino and keto acid interconversion and biotin dependant carboxylases. Both are central to energy pathways.

I'm still REALLY a novice and I swear I'm not arguing for the sake of argument. Doing my write-up in no way made me an expert in this stuff - I always feel like one of the proverbial blind men with the elephant! My source is Wikipedia, but it says that oxaloacetate produces oxalate via oxaloacetase, so the two are connected.

-J

 

[JaimeS]

Could an answer to the diet dilemmas in this thread be a low-carb diet but add resistant starch?

Good point, @South !

-J

 

[Gondwanaland]

We do have the RS challenge thread .
A derivation from it is the Clostridium butyricum thread.
A derivation from it is the Oxalate dumping thread.
And the circle is closed

 

[JaimeS]

@Gondwanaland - you made me literally LOL!

The longer I'm here on PR the more I'm absolutely floored by the work/thought people put into figuring out what's going on, and just the vast repository of knowledge that is this place.

Sometimes I think it all has to be organized, but then I think what madness that would be.

-J

 

[Gondwanaland]

Sometimes I think it all has to be organized, but then I think what madness that would be.

You know there is a thread for that too

 

[JaimeS]

I knoowwww, I commented that it was too huge an undertaking, and that it might prioritize certain voices over others...

 

[Vasha]

Could an answer to the diet dilemmas in this thread be a low-carb diet but add resistant starch? Resistant starch is not digested by the human gut, but IS digested by the microbiota. . . .
http://forums.phoenixrising.me/inde...ge-is-it-the-key-weve-been-looking-for.26976/

We do have the RS challenge thread .
A derivation from it is the Clostridium butyricum thread.
A derivation from it is the Oxalate dumping thread.
And the circle is closed

And actually, when I had the energy, I've spent the last couple of days trying to make it through those threads looking into what @South suggested! I began with the RS thread (which is impossible to get through all the way at this point) and went into derivations.

I ended up with one more that would also close the circle:
the thread on whether supplements work at all

I was feeling pretty discouraged about my own understanding, but wow is the collected information impressive!

Thanks @Snow Leopard for the links to the other articles!
It is overwhelming, but I'm going to stick with my sig line for now.

Vasha

 

[Vasha]

@JaimeS @Gondwanaland

Benoit Mandelbrot should have studied PR.

But seriously, it's amazing. Feeling pretty grateful for all the time and brainspace people share.

Vasha

 

[JaimeS]

Benoit Mandelbrot should have studied PR.

LOL! I'm intensely grateful for PR. I think that the most important (non-concrete) thing it's given me (you've all given me) is the ability to make progress through hard work. Feeling helpless is the worst!

-J

 

[Tammy]

The longer I'm here on PR the more I'm absolutely floored by the work/thought people put into figuring out what's going on, and just the vast repository of knowledge that is this place.

You took the words right out of my mouth....... Heroes and pioneers in my book.

 

[Strawberry]

@brenda . A ways back (somewhere in this thread) you said you couldn't eat 3 tbsp of coconut oil. *whispers* make it into chocolate! Equal parts coconut oil and cocoa, and flavor with honey to taste. It is hard to stop eating it.

 

[alicec]

Actually, I do wonder what sorts of symptoms accumulation of oxaloacetate et al could cause. Perhaps what we call "oxalate issues" is in part this stuff.

Well oxaloacetate is certainly an intermediate in many metabolic processes as well as the Kreb's cycle - urea cycle, gluconeogenesis, amino and fatty acid synthesis. Its role is always as a substrate/end-product of transaminations - those ubiquitous B6-dependant enzymes again. Accumulation of oxaloacetate could certainly signal global problems with them.

But you are right, there is a direct connection with oxalate that I keep forgetting about - the glyoxylate cycle in the peroxisome. This pathway, which has only been recognised in mammals relatively recently and is not well understood, truncates the Kreb's cycle. Instead of being converted to alpha ketoglutarate, isocitrate gets converted to glyoxylate via isocitrate lyase, glyoxylate is converted to malate via malate synthase, malate continues to oxaloacetate as in the full Kreb's cycle.

Malate synthase requires acetyl CoA, so if there are problems supplying this, glyoxylate can accumulate in the peroxisome. Here it may be converted to oxalate by glycollate oxidase or it might travel into the cytosol and be converted by LDH, as is @Gondwanaland's favourite diagram and as discussed on the oxalate thread.

The really interesting thing that is directly pertinent to what has been discussed on this thread, is what induces isocitrate lyase and thus starts the process in train. It seems that the glyoxylate cycle is a stress pathway and one particular stressor that induces this enzyme is burning of fat for energy. I don't know any real detail about this but it seems to be another reason to avoid a ketogenic diet.

 

[alicec]

My source is Wikipedia, but it says that oxaloacetate produces oxalate via oxaloacetase,

That is a fungal enzyme, fairly sure this reaction doesn't happen in mammals, but there is indeed a connection - see my post above.

 

[alicec]

Could an answer to the diet dilemmas in this thread be a low-carb diet but add resistant starch?

Well many of us who have worked our way through the entire resistant starch challenge thread did try that. For many of us even small amounts of RS2 in the form of raw potato starch were simply intolerable. It is just too potent.

We certainly need resistant starch to feed our microbiota but food seems to be a more tolerable way of at least starting to introduce it into the diet.