Metabolic Trap In ME/CFS

[Travis]

@haidut figured you may be interested in this discussion, given that you've kept up with the quality research on hypometabolism in CFS.

@Travis and @SB4 you may be interested too

This is interesting, but an Italian researcher states that indolamine dioxygenase-2 activity is of relative minor importance when compared to that of indolamine dioxygenase-1 and tryptophan diooxygenase.

'One major question is in fact – Why does AhR need two distinct sources of the ligand kynurenine to become activated, namely, tryptophan 2,3-dioxygenase (TDO₂) and indoleamine 2,3-dioxygenase (IDO₁)? (The third known tryptophan catabolic enzyme, IDO₂, has limited catalytic activity relative to the two others.).' ―Puccetti​

Although Italians generally have high oleamide and lycopene concentrations, they can actually be somewhat credible at times (lol, just kidding—Italians are never credible). I had found this study because I had wondered if indolamine dioxygenase-2 was also under transcriptional regulation by cortisol, yet this appears to be not the case: Tryptophan dioxygenase-2 appears the tryptophan catabolic enzyme under the control of corticosteroids, while indolamine dioxygenase-1 appears to be degraded by interleukin-6. Low kynurenine and niacin concentrations via tryptophan dioxygenase-2 could be epiphenomenon of low cortisol consistently noted in chronic fatigue (Cleare, 2001), yet contributions from interleukin-6 seem more speculative due to the absence of much consistency between cytokines and chronic fatigue.

Taking niacin could sound like a good idea on account of its precursor role for NADH, yet niacin is also known to spare indoles by negating the necessity of its own formation via tryptophan. Excessive niacin also removes methyl groups from the body before it's excreted as N-methylnicotinic acid, the primary niacin metabolite, an act that might reduce the amount of epinephrine and acetylcholine synthesized. It had become well-known among cardiologists in the 1980s that high-dose niacin could lead to high homocysteine concentrations, an observation that had been explained by the depletion of the 'methyl pool' and verified in rodents (Basu, 2002).

 

[energyandstruct]

This is interesting, but an Italian researcher states that indolamine dioxygenase-2 activity is of relative minor importance when compared to that of indolamine dioxygenase-1 and tryptophan diooxygenase.

'One major question is in fact – Why does AhR need two distinct sources of the ligand kynurenine to become activated, namely, tryptophan 2,3-dioxygenase (TDO₂) and indoleamine 2,3-dioxygenase (IDO₁)? (The third known tryptophan catabolic enzyme, IDO₂, has limited catalytic activity relative to the two others.).' ―Puccetti​

Although Italians generally have high oleamide and lycopene concentrations, they can actually be somewhat credible at times (lol, just kidding—Italians are never credible). I had found this study because I had wondered if indolamine dioxygenase-2 was also under transcriptional regulation by cortisol, yet this appears to be not the case: Tryptophan dioxygenase-2 appears the tryptophan catabolic enzyme under the control of corticosteroids, while indolamine dioxygenase-1 appears to be degraded by interleukin-6. Low kynurenine and niacin concentrations via tryptophan dioxygenase-2 could be epiphenomenon of low cortisol consistently noted in chronic fatigue (Cleare, 2001), yet contributions from interleukin-6 seem more speculative due to the absence of much consistency between cytokines and chronic fatigue.

Taking niacin could sound like a good idea on account of its precursor role for NADH, yet niacin is also known to spare indoles by negating the necessity of its own formation via tryptophan. Excessive niacin also removes methyl groups from the body before it's excreted as N-methylnicotinic acid, the primary niacin metabolite, an act that might reduce the amount of epinephrine and acetylcholine synthesized. It had become well-known among cardiologists in the 1980s that high-dose niacin could lead to high homocysteine concentrations, an observation that had been explained by the depletion of the 'methyl pool' and verified in rodents (Basu, 2002).

I thought the problem was specifically that IDO1 doesn't work if tryptophan gets too high, because it is substrate inhibited or something.

 

[Travis]

I thought the problem was specifically that IDO1 doesn't work if tryptophan gets too high, because it is substrate inhibited or something.

Oh, well IDO₂ inhibition would be more of a problem assuming that Dr. Puccetti is correct in stating that '[IDO₂] has limited catalytic activity relative to the two others.' I had got the impression that IDO₂ was the prime concern from this quote below, yet I haven't read the article though I intend to:

'The theory is that MECFS kicks in if you have a broken IDO2 (predisposition to disease) and then somehow (often during an infection) you get to the level of tryptophan that causes IDO1 to quit and walk off the job. There's no (easy) way back.'​

 

[Astolfo]

I couldn't understand well actually. Do I have excess IDO or low IDO? I had read that inhibiting IDO can reverse kynurenine induced encephalopathy.
Also if IDO is underactive in my case, taking aspirin would be bad idea, isn it? COX-2 inhibitors inhibit IDO as well.

 

[energyandstruct]

Out of curiosity, I checked my lab results from Jan 2007 when I was feeling 80% recovered and could exercise, and then compared them with the same test (different lab though) in May 2010, just under 3 years after I relapsed. In 2007, the kynurenate was 1.4, at the high side of normal; in 2010, as kynurenic acid, it was 0.9, the low side of normal. This would 'fit' his thesis; but the odd thing is that when I felt like crap and could barely walk in 2010, all the test results were normal, although all consistently low. When I felt great in 2007, so many metabolities were out of range, that it was clear there were some major issues with BCAA and tryptophan metabolism, fatty acid oxidation, hepatic conjugation, glutathione wasting, and intestinal dysbiosis. The overwhelming fatigue is a compensatory mechanism to slow things down, which is why most attempts to speed up the metabolism (whether with cortisol, or thyroid, or methyline blue) backfire.

Agreed. I have started mold avoidance and think introducing thyroid now will help whereas at didn't earlier