• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

High Need For Folate?

Gondwanaland

Senior Member
Messages
5,092
Another intresting bit on methylation /xanthine oxidase inhibition:

https://en.wikipedia.org/wiki/Uric_acid#Solubility
Solubility of urate salts (grams of water per gram of compound)
Compound Cold water Boiling water

UrateSolubilityWiki.jpg

The figures given indicate what mass of water is required to dissolve a unit mass of compound indicated. The lower the number the more soluble the substance in the said solvent.[5][6][7]
 

Gondwanaland

Senior Member
Messages
5,092
Folic acid does not inactivate xanthine oxidase.: This study concluded that the apparent inactivation of xanthine oxidase by folic acid in the report by Lewis et al was caused by the slow binding of contaminating pterin aldehyde.
Apparently it DOES o_O
Interaction of Milk Xanthine Oxidase with Folic Acid
INHIBITION OF MILK XANTHINE OXIDASE BY FOLIC ACID AND SEPARATION OF THE ENZYME
INTO TWO FRACTIONS ON SEPHAROSE 4B/FOLATE GEL*
(Received for publication, April 2, 1986)
Takeshi Nishino and Keizo Tsushima
From the Department of Biochemistry, Yokohama City University School of Medicine, Urafune-cho 2-33, Minami-ky
Yokohama 232, Japan

Inhibition of xanthine oxidase by folic acid was reexamined after complete removal of the contaminant which was responsible for time-dependent inactivation (Lewis, A. S., Murphy, L., Mcalla, C., Fleary, M., and Purcell, S. (1984) J. Biol. Chem. 259,12-15; Spector, T., and Ferone, R. (1984) J. Biol. Chem. 259, 10784-10786). From turnover experiments using stopped flow equipment with a limited amount of xanthine and excess oxygen, and from kinetic analyses with an oxygen electrode, folic acid was found to be an inhibitor of xanthine oxidase. The inhibition was competitive with xanthine with a Ki value of 4.2 X lo-‘ M. From the behavior of the enzyme in affinity chromatography
using a Sepharose 4B/folate column, folic acid was also confirmed to be a competitive inhibitor of xanthine oxidase. When enzyme which had been pretreated with oxipurinol was applied to the affinity column, two fractions of xanthine oxidase were separated. The first fraction was found to contain the fully active form (double-active dimers) from the analyses of spectral changes on addition of xanthine, oxipurinol titration, and ESR slow signal, whereas the second fraction was assumed to contain mixed dimers and double-inactive dimers. The ratio of the content of the first fraction to that of the second fraction supports the hypothesis that there are three enzyme species and that there is no interaction either in catalytic activity or in sulfuration or desulfuration reactions between the two subunits.
 

alicec

Senior Member
Messages
1,572
Location
Australia
Isn't folate and folic acid different?

Yes but there is overlap in how they react and are used in the cell.

Folic acid is recognised by the transporter that takes natural folate into the cell - in fact is has higher affinity for these receptors and can outcompete natural folate.

Once inside the cell folic acid is recognised by the enzyme dihydrofolate reductase (DHFR) which processes it in a two step reaction. First it converts folic acid to dihydrofolate (DHF), then it converts DHF to THF. This latter reaction is the normal reaction for this enzyme but structural similarities mean that it can recognise folic acid and do the first conversion also.

The first step, ie processing of folic acid, is very slow in everyone and particularly so in some people. In other words, the enzyme has more trouble with the folic acid substrate than it does with its normal substrate DHF. This is probably the reason that folic acid accumulates.

Folic acid also inhibits this second step, ie conversion of DHF to THF, so DHF accumulates. DHF in turn inhibits other enzymes in the folate cycle, eg MTHFR, SHMT1, TS and enzymes involved in purine metabolism.

In other words, while folic acid acts similarly to natural folate, it is not equivalent.

In the experiments described with xanthine oxidase, folic acid was shown to bind to and inhibit the enzyme. It is a reasonable assumption that natural folate would do the same thing but whether there are any subtle differences in the reaction is unknown.
 

Gondwanaland

Senior Member
Messages
5,092
Folic acid is recognised by the transporter that takes natural folate into the cell - in fact is has higher affinity for these receptors and can outcompete natural folate.
Many people reported intolerance to natural folate from vegetables while on high dose methylfolate. So apparently it also has the ability to block natural folate at some point.
 

alicec

Senior Member
Messages
1,572
Location
Australia
So apparently it also has the ability to block natural folate at some point.

Methylfolate is a natural folate. It is the predominant form circulating in blood and is a major form in vegetables. Yes the vegetable form has a polyglutamate tail but this is cleaved off in the intestine so the form taken up into the blood is identical to the supplement.

Freddd and others reported that supplemental folinic acid, along with folate rich vegetables, seemed to interfere with the beneficial effects of supplemental methylfolate.

The reason for this is unclear. Possibly with the folinic supplementation, there is an inability to process it efficiently and it accumulates. Folinic can definitely inhibit some other folate pathways.

With vegetables, many people think that folinic is the major folate form and assume that the same mechanism is happening. However this is not really correct. The folate forms in vegetables are variable and some do have significant amounts of folinic, but methylfolate is far and away the dominant form in almost all high folate vegetables.

It's a bit hard to know what is going on with the vegetable problem.
 
Last edited:

charles shepherd

Senior Member
Messages
2,239
MEA INFO ON FOLIC ACID DEFICIENCY AND ME/CFS:

There are a number of reasons why folic acid deficiency can occur:

1 having a diet that is lacking in folic acid containing foods (eg greens, cereals) - the commonest reason

2 gastrointestinal diseases such as coeliac disease, which reduce the absorption of this vitamin. This might be relevant because coeliac disease can cause symptoms that are similar to ME/CFS - which is why screening for coeliac disease should form part of the clinical assessment when a diagnosis of ME/CFS is being queried.

3 pregnancy

4 some types of medication

It should be noted that one small research study has reported that low folate levels can occur in ME/CFS:
http://www.ncbi.nlm.nih.gov/pubmed/8255470

Folic acid deficiency can cause a specific type of anaemia where there are large red blood cells - megaloblastic anaemia

So a doctor should be trying to find out why folic acid deficiency is happening - in addition to treating the deficiency

If a GP cannot provide a satisfactory answer you should then be referred to a hospital specialist for further assessment

Good information on folic acid deficiency:

http://patient.info/health/folic-acid-deficiency-anaemia

http://www.mayoclinic.org/drugs-supplements/folate/evidence/hrb-20059475
 

alicec

Senior Member
Messages
1,572
Location
Australia
What vegetables are high in folinic?

Here is one study and I have uploaded a PDF of another.

The first one looks at a variety of vegetables. Look at Table 1 to see the breakdown of different vitamers. Folinic is 5-HCO-H4 folate. Methylfolate is 5-CH3-H4 folate.

You will see that a number of vegetables have significant amounts of folinic but not nearly as much as methylfolate . These include things like spinach, broccoli, brussel sprouts, savoy cabbage, cauliflower, kale.

The PDF specifically looks at Asian greens.

Look at Fig 9. 5 MeTHF is methyl folate, 5 formylTHF is folinic. Here you will see that many have almost as much folinic as methylfolate, with mizuna having more folinic than methylfolate.

So if you were eating a lot of Asian greens and experienced problems, it could be the folinic interfering. With other vegetables it is less clear.
 

Attachments

  • folate content asian vegetables.pdf
    1.2 MB · Views: 29

alicec

Senior Member
Messages
1,572
Location
Australia
using atoms from ..... as well as the coenzyme tetrahydrofolate.

The formyl (CHO) group of 10 formyl THF is donated in these reactions; THF is regenerated.

10 formyl THF (not to be confused with 5 formylTHF which is folinic) is formed from THF by the enzyme MTHFD1 (or MTHFD1L in the mitochondrion).
 

Gondwanaland

Senior Member
Messages
5,092
It's an amino acid, not a purine.
Now I see what you mean. Glycine is a direct purine precursor.

http://library.med.utah.edu/NetBiochem/pupyr/pp.htm#Syn pu
De novo synthesis of both purine and pyrimidine nucleotides occurs from readily available components.
De Novo Synthesis of Purine Nucleotides
We use for purine nucleotides the entire glycine molecule (atoms 4, 5,7), the amino nitrogen of aspartate (atom 1), amide nitrogen of glutamine (atoms 3, 9), components of the folate-one-carbon pool(atoms 2, 8), carbon dioxide, ribose 5-P from glucose and a great deal of energy in the form of ATP. In de novo synthesis, IMP is the first nucleotide formed. It is then converted to either AMP or GMP.
pupy12.gif