I was thinking in terms of inducible NOS (NOS2), which isn't regulated like eNOS and nNOS. Increased arginine concentrations are definitely going to result in increased NO production by iNOS, subject to obvious physiological considerations.
I have to study this some more. I started looking into it, but it will take some time for me to get a handle on it.
I think the most important thing about the subject is that we need to do what we can to avoid producing a lot of ammonia, even if BH4 isn't affected by it, because is is costly in terms of ATP. I am thinking of what might be the best way to do this. Limiting protein, especially meat protein to a certain extent would be helpful, but I think you would want to take methionine and some NAC to make sure that you are not short in methylation or glutathione synthesis. Limiting meat protein is difficult for people who have trouble with glucose metabolism, though, so that might not work for everyone.
It's true that glutathione is also a peroxynitrite scavenger, but with respect to the specific action of maintaining the integrity of BH4 during its catalytic role of one-electron transfer for NOS activity, methylfolate has the preeminent role of peroxynitrite scavenger during that process.
So far I can't find anything to convince me that the role of folate in scavenging peroxynitrite is not related to it's role in NADPH synthesis, either by producing BH4 or by recycling glutathione. Don't get me wrong - I would be delighted if folate
could reduce superoxide or scavenge peroxynitrite in another way because I am looking for supplements that could do that very thing
without using NADPH.
Keep in mind that when a study says that 5-MTHF did something in a study, what they mean is that 5-MTHF was the form of folate they used in the study, it doesn't necessarily mean that 5-MTFH was the form that accomplished whatever the study said that the folate did. The form of folate molecules changes rapidly all the time in the cell. So far I haven't seen anything that shows that they proved that 5-MTHF was the form that did the job. So it could easily be another reaction, such as the MTHD or the dihydrofolate reductase that helped lower peroxynitrite.
One reason I think it is so important to know
how folate reduces peroxynitrite is because if a person has an inhibited electron transport chain and is using the folate cycle for ATP recycling, then adding more folate can limit the availability of B6 if the SHMT enzyme is working well in that person. This is what happens to my son, D (for depression). He has been working on rest periods for over a week, and he hasn't felt depressed since I lowered his folate to 1 mg per day. Today I decided to try giving more folate, because I thought that if he was using the rest periods it might not drain his B6 enough to cause depression and maybe it would have a net effect of lowering ROS. Well, he got depressed again, but not too badly, since it was only 1.6 mg extra.
Even if a person does not get obvious symptoms from the lack of B6 availability, it will affect their ability to make heme, which is required in the electron transport chain and for the synthesis of catalase, and so a lack of available B6 will increase oxidative stress.
I suspect that the studies showing a peroxynitrite scavenging effect of folate might only apply when there is not a shortage of ATP, and the folate cycle is not being used as a backup ATP source. Also, if the ETC is not inhibited, and ATP synthesis is not a problem, then the ammonia produced by the glycine decarboxylase, which is inevitable when the folate cycle is going top speed, is not going to be a problem.
I know that you have seen my folate cycle illustration but I put it here for those reading this thread who have not seen it to show what I am talking about.
In someone who is low on ATP and NADPH these pathways will be pulled more towards the directions I have in the red arrows.
Anyway, my point is that I think it is very important to be sure that folate will really work as a net antioxident in people with mitochondrial failure, because taking a lot of folate (maybe more than 2 mg a day, maybe a little less) might increase problems in other areas for those individuals. I haven't seen tests on this that were done with people with mitochondrial dysfunction, have you?
If you have the time maybe you can give me the most convincing reference that you have to support the idea that folate has a role as a peroxynitrite scavenger that does not rely on its ability to generate NADPH and/or BH4. I have spent quite a bit of time looking and I haven't found a good one, yet.