OAT, PLEASE INTERPET

[Valentijn]

Yasko has a lot to answer for in this respect. She seems to have kicked off a lot of the myths about BH4 and its links to the folate cycle. Her misreading of research and diagrams has been endlessly repeated.

I suspect her diagrams find it convenient to omit most genes which aren't on her test. And as her test seems to be based on convenience and the creation of non-existent problems, rather than actual relevance to methylation, it's not surprising that most of the folate cycle is missing.

As a side note, a mainstream MD has attempted to Yasko my mother just in the past few days. Fortunately she asked me about it first, and I was able to explain that most of it is quite meaningless. She forwarded my nice comments back to the doctor, who did back off from it, but still thinks that the slightly better version of VDR Taq (Yasko's +/+) is a reason to closely monitor Vitamin D levels in her patients

It's incredible how far misinformation can spread with sufficient enthusiasm and savvy marketing

 

[Jimbo39]

I suspect her diagrams find it convenient to omit most genes which aren't on her test. And as her test seems to be based on convenience and the creation of non-existent problems, rather than actual relevance to methylation, it's not surprising that most of the folate cycle is missing.

I can see how someone, like me, who is totally obvious can buy into this. The reason I started looking into other sites was because of the many supplements she touts. I simply can't afford them.

As a side note, a mainstream MD has attempted to Yasko my mother just in the past few days

Ha ha! You've been Yasklo'd.

 

[Jimbo39]

@alicec Quick question, the first diagram shows two overlapping cycles. Are these the folate and methionine cycles?

 

[Jimbo39]

I weki'd NADPH. Didn't understand most of what was said other that it's an electron donor. So NADPH gives up an electron to convert BH2 to BH4? At the MTHFR site NAD accepts an electron to convert to NADPH? I can see how people with a MTHFR defect would have low BH4 levels or is this too broad of an assumption?

Still waiting for my 23 and me results.

 

[Jimbo39]

I meant MTHFD not MTHFR. So much for my assumption.

 

[Jimbo39]

5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is the substrate used by the enzymemethylenetetrahydrofolate reductase (MTHFR)[1][2] to generate 5-methyltetrahydrofolate (5-MTHF, or levomefolic acid).

5,10-CH2-THF can also be used as a coenzyme in the biosynthesis of thymidine. To be specific, it is the C1-donor in the reactions catalyzed by thymidylate synthase and thymidylate synthase (FAD). It also acts as a cofactor in the synthesis of serine from glycine via the enzyme serine hydroxymethyltransferase.


Ok, 5-10 methylene THF seems to be very important as it is used:

1. To feed into MTHFR which reacts with 5 methylfolate and MTR to feed THF

2. To react with TYMS to feed DHF. Is TYMS thymidine? So dUMP reacts with TYMS to produce dUTP. Is this called thymidylate synthase? I read that too much dUTP causes DNA damage.

3. To react with SHMTI to feed into THF.

Please correct me if I'm wrong.

 

[Jimbo39]

So 5-10 methenyl THF reacts with SHMTI with the help of cofactor B6 to produce folinic which reacts with MTHFS with cofactors ATP and Mg to complete the cycle. Is there a net energy loss in this reaction?

 

[alicec]

the first diagram shows two overlapping cycles. Are these the folate and methionine cycles

The diagram shows different aspects of the folate cycle. On the right-hand side, the MTR reaction, where homocysteine is converted to methionine, is the point where the methylation cycle would intersect.

Because the diagram is concentrating on the folate cycle, it emphasises that at this point, MeTHF is converted to THF, which re-enters the folate cycle.

The diagram doesn't show the consequence of the homocysteine to methionine conversion, generation of SAMe, which is then used in a variety of methylation reactions, nor does it show the regeneration of homocysteine so the cycle can continue.

These reactions constitute the methylation cycle which would normally be shown as yet another cycle, intersecting at MTR.

 

[Jimbo39]

At the MTR site it shows Zn as a cofactor but shows NO with a T above it. Does this mean nitrous oxide blocks this enzyme? If so folic acid blocks DHFR. Since you mentioned folic acid being a laboratory creation, is the diagram suggesting not to supplement with this? My old doc said I need to supplement with arginine since I'm low in it 11(10-64). Is this ill advised since it produces NO?

That's all I can handle for now.

 

[alicec]

I weki'd NADPH. Didn't understand most of what was said other that it's an electron donor.

NADPH is the major source of electrons to drive anabolic (synthetic) pathways in the cell. Here is a fairly simple explanation of its role.

The relative abundance of the NADPH form of the molecule (as opposed to its oxidised form, NADP) drives these oxidation-reduction (or redox) reactions forward.

While it is not the main source of NADPH, the reactions driven by MTHFD are an important source of NADPH in the cell.

NADPH seems to act as a global barometer of cellular fuel status. When it is high, cellular pathways are shifted to growth and repair. When it is low, synthetic pathways fall to baseline survival mode.

So it is not just BH4 which is impacted but the entirely of redox reactions in the cell.

 

[alicec]

Ok, 5-10 methylene THF seems to be very important

What you say is correct, but also this molecule is converted to 5,10 methenyl THF by MTHFD, producing a significant amount of NADPH, as discussed above. Further along this pathway, the complete oxidation of 10 formyl THF to THF generates more NADPH.

The significance of this area of flux through the folate cycle is often overlooked.

Is TYMS thymidine

TYMS is the enzyme thymidylate synthase.

 

[alicec]

Is there a net energy loss in this reaction?

Yes.

The way you describe the reaction is not wrong but it is probably more correct to say the 5,10 methenyl THF is converted to folinic acid by the enzyme SHMT1, which uses B6 as a cofactor. In other words it is the enzyme doing the work of converting a substrate (5,10 methenyl THF) into a product (folinic acid).

The enzyme MTHFS then converts folinic back to 5,10 methenyl THF, in an ATP dependant (and ATP consuming) reaction. Whenever you see ATP, read MgATP - the two always go together.

 

[alicec]

At the MTR site it shows Zn as a cofactor but shows NO with a T above it. Does this mean nitrous oxide blocks this enzyme

Yes, nitric oxide (NO) blocks this step (nitrous oxide is N2O).

If so folic acid blocks DHFR. Since you mentioned folic acid being a laboratory creation, is the diagram suggesting not to supplement with this?

Yes and yes, especially if you happen to be one of the people who has difficulty making the folic acid conversion.

My old doc said I need to supplement with arginine since I'm low in it 11(10-64). Is this ill advised since it produces NO?

Nitric oxide plays an important role, among other things, in keeping blood vessels flexible - it is a very useful molecule, but too much nitric oxide can be a problem, including blocking some enzymes.

It's all about balance.

I really don't know if supplementing arg will even do what people think it will do. There is this pesky problem of feedback inhibition. Arg is also used in the urea cycle which is very tightly regulated. Increasing it substantially might just result in down regulation.

 

[Jimbo39]

The diagram shows different aspects of the folate cycle. On the right-hand side, the MTR reaction, where homocysteine is converted to methionine, is the point where the methylation cycle would intersect.

Yes, after studying the second diagram, I can see that now. I need to less hasty with my questions.

 

[Jimbo39]

NADPH is the major source of electrons to drive anabolic (synthetic) pathways in the cell. Here is a fairly simple explanation of its role.

 

[Jimbo39]

NADPH is the major source of electrons to drive anabolic (synthetic) pathways in the cell. Here is a fairly simple explanation of its role.

This is way easier to understand than Wekip. I've always thought of oxidation as something breaking down i.e. rust. But it's actually a molecule gaining an electron (iron +oxygen =rust). So in our bodies, when a molecule gains an electron, it can become positively charge or a free radical?

 

[Jimbo39]

What you say is correct, but also this molecule is converted to 5,10 methenyl THF by MTHFD, producing a significant amount of NADPH, as discussed above.

I can see this in the first diagram. So the cycle is complete and starts again.

Further along this pathway, the complete oxidation of 10 formyl THF to THF generates more NADPH.

Yes, it takes place in the little cycle. Looks like ATP is involved.

 

[Jimbo39]

he way you describe the reaction is not wrong but it is probably more correct to say the 5,10 methenyl THF is converted to folinic acid by the enzyme SHMT1, which uses B6 as a cofactor. In other words it is the enzyme doing the work of converting a substrate (5,10 methenyl THF) into a product (folinic acid).

This makes a lot more sense.

 

[Jimbo39]

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

 

[Jimbo39]

NADPH seems to act as a global barometer of cellular fuel status. When it is high, cellular pathways are shifted to growth and repair. When it is low, synthetic pathways fall to baseline survival mode.

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