OAT, PLEASE INTERPET

[alicec]

So on the downward part of the cycle, THF to 5-10 methynylene THF, would you say the molecules are being reduced? And on the upward swing, oxidized?

Not all reactions are oxidoreductions. The two that convert THF to 5,10 methylene THF are aminotransferase and decarboxylase reactions, not oxidoreductions.

It doesn't really matter - ie you don't need to worry about that sort of detail unless you happen to like biochemistry.

It is important to understand a little about oxidoreductions to appreciate how NADPH/NADP+ (and also NADH/NAD+) work, but beyond that, not necessarily.

 

[alicec]

Is there a way to test for NADPH levels? I don't suppose there's much you can do if it's low anyway.

There may be some sort of test, I'm not sure. But NADPH itself is not the problem. It is a cofactor, a messenger; it can only do its job if many other components are in place.

In this respect, if you haven't already caught up with it, the NADPH problem is at the heart of the recent ground-breaking publication on the metabolic signature of CFS, discussed here and in two related threads.

 

[Jimbo39]

Not all reactions are oxidoreductions. The two that convert THF to 5,10 methylene THF are aminotransferase and decarboxylase reactions, not oxidoreductions.

Is oxidoreduction also known as redox? Are aminotransferase and decarboxlase know as formylation? in the link you gave me, aromatic amino acids are low in people with CFS. It is needed for formylation.

It doesn't really matter - ie you don't need to worry about that sort of detail unless you happen to like biochemistry.

It's not so much I'm interested in biochemistry tho I find it fascinating. Up until 2-3 years ago I put my health in the hands of traditional docs with disastrous results. 2 years ago, I started reading researching different opinions on treating CSF and ended up taking over 30 supplements (I've been Yasklo'd) without any idea what they were doing for me. I suppose I want a more targeted approach for me individually rather than a shotgun approach. For this I need an understanding of the biochemical reactions that take place in our bodies and how they apply to me based on test results and symptoms.

 

[Jimbo39]

There may be some sort of test, I'm not sure. But NADPH itself is not the problem. It is a cofactor, a messenger; it can only do its job if many other components are in place.

In this respect, if you haven't already caught up with it, the NADPH problem is at the heart of the recent ground-breaking publication on the metabolic signature of CFS, discussed here and in two related threads.

Yes, and I can see that metabolic cofactors are severely depressed in those with CFS and how it would lead to less production of NADPH. The thought of a hypo metabolic state leading to a survival mode fits right in with us not having any energy other than what's absolutely necessary.

From what I read, it seems that a hypo metabolic state can be induced by environmental stress. Trauma, infection, heavy metals, pesticides, chronic stress? It seems that the body may "hard wire" itself to this condition and it would take a major intervention on our part to correct it. I can see where a multi pronged approach would be necessary. I.e. Gut, supplying the necessary cofactors, detox, antivirals, antibiotics, etc.

 

[alicec]

For this I need an understanding of the biochemical reactions that take place in our bodies and how they apply to me based on test results and symptoms.

Fair enough. Once you get used to the terminology you will find it gives a lot of clues. The name of an enzyme will often tell you what kind of reaction it catalyses. Wikipedia will usually give a general description first though will then probably lose you when it discusses mechanism of action.

It may be helpful for you to take a free online course in basic biochemistry that you can follow at your own pace. There could be something here

Is oxidoreduction also known as redox? Are aminotransferase and decarboxlase know as formylation? in the link you gave me, aromatic amino acids are low in people with CFS. It is needed for formylation.

Yes to the first, no to the second.

An aminotransferase transfers an amino group - NH2

A decarboxylase removes a carboxyl group - COOH

Formylation is the addition of a formyl group - COH. This reaction is important in parts of the folate cycle - formation of 10 formyl THF and 5 formyl THF. The enzyme names give a clue here - N(10) formylTHF synthetase (synthesis, by adding a formyl group to THF) and formyl THF dehydrogenase (removing a formyl group to produce THF from 10 formylTHF).

 

[Jimbo39]

The enzyme names give a clue here - N(10) formylTHF synthetase (synthesis, by adding a formyl group to THF) and formyl THF dehydrogenase (removing a formyl group to produce THF from 10 formylTHF).

That makes sense. Synthetase means adding, -ase means removing and transfertase means transferring.

Do you have a background in science or are you self taught?

 

[alicec]

Do you have a background in science

Yes my original training was in biochemistry and I spent all my working life in medical research.

 

[luminescencs]

I can see where a multi pronged approach would be necessary. I.e. Gut, supplying the necessary cofactors, detox, antivirals, antibiotics, etc.

I completely agree, Jimbo. I've been helped immensely with diet and customizing my own therapies by supporting my genetics. Doctors didn't have the time, so it took a lot of creative thinking.

Have you heard of SelfDecode?

It's an extremely thorough genetics analyzer. You just take your 23andme raw genetic data and upload it into the system. Then it gives you customized "fixes" for your 'bad' genes and explanations for all of your SNPs. I've tried every other genetic interpreter on the market (Prometheus, Genetic Genie, etc.) and was really disappointed because there weren't many actionable next steps for me once I uploaded my information. It all just felt like a waste.

Yes my original training was in biochemistry and I spent all my working life in medical research.

Alicec I noticed your post on another thread about genetics. I have a hunch it's something you would also really appreciate.

 

[Jimbo39]

completely agree, Jimbo. I've been helped immensely with diet and customizing my own therapies by supporting my genetics. Doctors didn't have the time, so it took a lot of creative thinking.

You said this much better than I could. Customized therapy

 

[Jimbo39]

@Valentijn

I'm trying to rap my head around SNPs. Apparently they are not mutations or defects? But variations. So if the gene pool they (SelfDecode) are referencing are of European decent, how would it impact those of other races?

 

[Jimbo39]

Incremental improvements in NADPH production could theoretically be supported by interventions directed at folate, B12, glycine, and serine pools, and B6 metabolism

Theoretically? I wonder if there have been any long term case studies?

 

[Jimbo39]

Flavin Adenine Dinucleotide (FAD) Was Decreased.
Plasma FAD was decreased in both males and females with CFS (Tables 2 and 3). FAD is synthesized from riboflavin (vitamin B2) and ATP. The gastrointestinal absorption, distribution, and transporter-mediated uptake of FAD are carefully regulated during health and disease (19). FAD is mobilized from tissues, increased in the plasma, and renal secretion is increased under conditions of stress or infection (20). FAD is an important cofactor for fatty acid oxidation and sterol synthesis and is required for activation and oxidation of vitamin B6 (pyridoxine); lipoic acid metabolism (E3 subunit) needed for pyruvate, alpha-ketoglutarate, and branched chain amino acid oxidation; vitamin A activation; 5-methyltetrahydrofolic acid synthesis; niacin and NAD synthesis; and glutathione reduction. Functional deficiency of riboflavin can be produced by dietary and environmental factors (21). Severe riboflavin deficiency can present with a plasma acyl-carnitine pattern similar to multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric aciduria type II (GAII) (22). GAII-like acyl-carnitine abnormalities did not appear in CFS patients.

This seems important to me as my Krebs cycle is "stuffed." Would my nonexistent AKG have something to do with a faulty limpoic acid metabolism? Supplement with ALA?

Or do I just need to supplement with cofactors to increase AKG?

 

[Jimbo39]

@alicec Earlier, in regard to arginine supplementation, you mentioned feedback inhibition and down regulation. I'm familiar with down regulation. For instance, benzo use causes GABA receptors to down regulate because there's a abundance of GABA in the body. What is feedback inhibition? In the case of arginine, would the cells say "we have enough" and signal the body to produce less?

I wonder if this would be the case for supplementing with 5HTP? I'm supplementing with other amino acids as well

 

[Valentijn]

Apparently they are not mutations or defects? But variations.

The technical term is polymorphisms, which puts the "P" in SNP. But "variant" seems to work better for us as laymen.

These polymorphisms are all technically mutations, because they represent changes in the DNA. People assume mutations are meaningful, but most mutations have no impact at all, and are completely normal. So they are definitely not defects.

Missense mutations and nonsense mutations occur in the exons (coding sections of genes) and do have an impact on the enzyme the gene produces in the body. Missense mutations occur when one amino acid is swapped with another. Sometimes the enzyme functions the same, but sometimes function is drastically altered. Nonsense mutations mean that the gene terminates the enzyme prematurely, which is usually quite significant, but sometimes isn't if it happens near the end of the gene.

SNPs in non-coding sections and in between genes shouldn't have an impact. If they do (outside of splicing sequences and similar), there really isn't an explanation for it. But genetic studies correlating SNPs with disease, personality traits, or symptoms, tend to have a lot of false positives, and correlations involving non-coding and intragenic SNPs are especially suspicious. They also aways have very small effect sizes, even if supposedly statistically significant, which doesn't help

I think Promethease includes effect size, or at least research links, but all other SNP-interpretation services completely fail to distinguish between serious mutations and irrelevant SNPs which have very little impact if they have any at all.

So if the gene pool they (SelfDecode) are referencing are of European decent, how would it impact those of other races?

Ethnicity shouldn't make a difference. But it doesn't make sense to use European reference samples when there are huge international samples available. By using European samples, it might make a SNP variation which is rare in Europeans look more important than it really is. But if it's common in other ethnicities, or in a combined group, it suddenly looks extremely unlikely that it could be causing problems in their customers, since billions of other people have the same variants.

 

[Jimbo39]

Going back to the folate cycle and the little cycle (purine), I appears that THF is syntased or synthesized by added ATP and is hydrogenized or brokendown to produce NADPH. So it appears that this is a way to convert ATP to NADPH. If I'm lacking in APT because of my stuffed Krebs cycle then NADPH production is compromised?

Some how 2 purine enzymes are produced, so there must be energy loss in this reaction? Purines are one of the hypo metabolites mentioned. Purine's metabolite adenosine, performs a number of critical functions. I didn't know its an inhibitory neurotransmitter (it's not listed in my NT test). This would explain,in part, my excitory state. Adenosine lowers BP hence my high BP? At any rate since its APT driven, I'm stuffed.

 

[Jimbo39]

Missense mutations occur when one amino acid is swapped with another. Sometimes the enzyme functions the same, but sometimes function is drastically altered.

Maybe this is why it's so hard to "retrain" the body to use the right enzymes. It seems almost impossible given the body has "hard wired" itself on a genetic level.

Nonsense mutations mean that the gene terminates the enzyme prematurely, which is usually quite significant, but sometimes isn't if it happens near the end of the gene.

I'm not sure what you mean by "terminate the enzyme prematurely". Does this mean before the enzyme can be used its terminated or the nonsense mutation ceases to produce it? What do you mean by "end of the gene".

Given that in CFS there are so many factors that would cause damage to DNA, knowing what your mutations are would play a big role in "treating" enzyme disfunction.

The biggest hypomatabolic in CSF is decreased lipid production. Would a compromised cell membrane cause DNA damage through oxidation, viruses, etc?

 

[Valentijn]

I'm not sure what you mean by "terminate the enzyme prematurely". Does this mean before the enzyme can be used its terminated or the nonsense mutation ceases to produce it? What do you mean by "end of the gene".

Basically the nucleobases (A C G T) in DNA can be directly "read" to spell out amino acids. A gene causes a bunch of amino acids to be put together in the right order to create a specific enzyme (such as MTHFR or MTRR, etc), which has a specific function in the body.

Each three nucleobase combination in the exons will translate directly to an amino acid, or to a "stop" command (TGA, TAG, or TAA). As an example, if there is a mutation in the combination which should code for cysteine (TGC or TGT) and a "TGC" is changed into a "TGA", the gene stops creating the enzyme which it should be creating.

But all the amino acids up to that point are in their normal position, so it might just be missing a little bit at the end which doesn't do much. Or it might be missing nearly all of the amino acids needed for the enzyme to do its job.

 

[Jimbo39]

Basically the nucleobases (A C G T) in DNA can be directly "read" to spell out amino acids.

Each three nucleobase combination in the exons will translate directly to an amino acid, or to a "stop" command (TGA, TAG, or TAA)

So there are 4 nucleobases but are only present in 3 nucleobase combinations in the exons (the coding section of the gene)? Each 3 letter combination produces a certain enzyme or amino acid?

But all the amino acids up to that point are in their normal position, so it might just be missing a little bit at the end which doesn't do much. Or it might be missing nearly all of the amino acids needed for the enzyme to do its job.

I think I'm beginning to understand. So if an amino acid is missing a little bit of the code at the end it doesn't affect the amino acid from doing its job?

 

[Jimbo39]

Ok I'm confused. So the 3 letter combination produces an amino acid and a combination of amino acids produces an enzyme?

If in your example cysteine TGC or TGT is changed to TGA (a stop command?) it prevents the gene from creating the enzyme? Is it safe to presume A nucleobases are stop commands?

 

[Jimbo39]

I'm on day 20 of my Valcycovir treatment. Sorry for jumping around from subject to subject. It's the way my hyperactive brain works.

I've noticed a significant cognitive improvement. My brain doesn't feel as inflamed/feverish.

Dr Lerner and Chia's reports were too sciency and lengthy for me but Myhill brought it down to earth. Myhill said viruses may be "below the radar" for tests to detect but could still result in chronic infection and even an autoimmune response as far as B and T cells are concerned. This would explain the inflammation (cytokines) and the low grade fever and the resulting fatigue as our are bodies are in a hypervigllant condition.

My doc prescribed Valcycovir for only 4 weeks followed up with herbal antivirals. This doesn't seem near long enough compared to Lerner's 18 month protocol. Perhaps the herbal AVs are just as potent? Chia uses the herb Oxymatrine. Anybody use this?

Anyway, I've decided to pay out of pocket to follow through with this because stopping treatment may result in resistance. My insurance actually picks up (50-80%) of the cost of tests.