Let me explain:
Trp is one way to make Kynurenine which is one way to make NAD. The metabolic trap hypothesis says we're not making kynurenine from Trp. So you might also expect low NAD (nicotinamide).
But instead the results on NAD are unclear. If we showed obviously diminished NAD, the theory that we can't make kynurenine would be supported. We don't show obviously diminished NAD, so the theory we can't make kynurenine is neither supported nor refuted.
(From Ben's comment above, it seems like Phair thinks maybe we can make nictotinamide from dietary niacin, so that could be an alternative pathway.)
I didn't see a role for Phenylalanine in the metabolic trap hypothesis. Can you explain?
First of all thanks for your reply. I've watched Phair's presentation and Ron's concluding remarks. I'll need to watch it again and a transcript might help.
I'm not confident that I know anything about ME/CFS now.
These papers indicate that intracellular phenylalanine levels (in blood cells) can be used to diagnose ME/CFS:
1) abstract:
https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper:
https://sci-hub.se/10.1039/C8AN01437J.
The intracellular levels of phenylalanine were increased in (blood cells in) people with ME/CFS. The method is based on Raman spectroscopy.
Chris Armstrong found that the levels of phenylalanine were reduced in blood plasma [
https://minerva-access.unimelb.edu....g Metabolomics CFS.pdf?sequence=5&isAllowed=y]. Chris proposed that there was a switch from using glucose to amino acids (such as phenylalanine) for cellular energy/ATP production; hence the lower levels in the blood plasma.
Fluge and Mella also proposed that there was a switch to using amino acids (including phenylalanine and tryptophan) for energy production [
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/].
As you pointed out the unique thing about tryptophan is that the enzyme which metabolises it at lower levels [IDO1] is substrate inhibited i.e. at higher tryptophan levels it ceases to work. As you also point out, phenylalanine doesn't have a substrate inhibited enzyme; therefore, it cannot cause a trap.
Possibly the above method, i.e. Raman spectroscopy, could be used to see if intracellular tryptophan levels are increased in ME/CFS - Phair's theory. I think Ron Davis/Phair point out that the levels of tryptophan are normally very low; so it may not be possible to measure intracellular tryptophan levels using Raman spectroscopy.
Possibly the high intracellular levels of phenylalanine in ME/CFS, and very low levels in blood plasma, indicate that these amino acids (including tryptophan) are being concentrated in the cell - i.e. as an energy source in ME/CFS [Armstrong, Fluge and Mella ]. Accumulating tryptophan, beyond the levels at which IDO1 functions, would set the trap.
All conjecture; measuring intracellular tryptophan levels would seem to be the way forward. Maybe that would be possible with Raman spectroscopy.
One thing Ron said i.e. that this may be a common path to autoimmunity [low kynurenine?]; therefore there may be funding for ME/CFS research. Also, I seem to recall that ME/CFS was used as a control group in Gulf War Syndrome and Lyme; maybe this will also help to get funding for ME/CFS research.
Thanks again for your comments.
