Hi Dbkita,
Understood. To be clear though I was implying that the 81% probably can mobilize folinic acid at some level (they used big dosages if I remember right). And that the 19% left over may NOT be able to do so.
I do and do understand exactly that. I was speculating that perhaps the slowness of processing itself could be a source of some level of insufficiency as the RATE of conversion couldn't keep up with the rate of demand. It would make sense in that 200mcg of l-methylfolate can't keep up with the folate demand it starts. It could be that the more effective the folinic acid the bigger the donut hole insufficiency it starts. That's one problem with folinic acid from one viewpoint anyway, that one doesn't know what is going on, there are too many possibilities.
more importantly SHMT2 in the mitchondria.
Can you explain that please? What would the effect be? I was wondering what difference methylfolate makes for AdoCbl. Would this be perhaps some part of that connection?
There are two isoforms for SHMT. SHMT1 in the cytosol runs the reversible reaction of serine +THF = glycine + 5,10 methylene THF. In the mitochondria the isoform is SHMT2. This preferentially drives the forward reaction of serine + THF = glycine + 5,10 methyleneTHF (the precursor to 5mthf).
The SHMT1 enzyme is part of a system to make sure the cell has ample THF hanging around but also enough 5,10 methyleneTHF and helps the SHMT2 enzyme makes glycine (very important). A secondary function of SHMT1 is to make intracellular folinic acid (5 formyl thf) from 5,10
methenylTHF (not
5,10 methylene THF) if there is sufficient glycine (meaning the forward primary reaction is working well already) and place it in store as a buffer for down the line production of thymidine, etc.
See:
http://www.ncbi.nlm.nih.gov/pubmed/2201683
I have to assume this takes place at another active site on the enzyme than the reversible serine-glycine site but maybe I am wrong. Anyways, MTHFS taps this store to re-make 5,10-
methenyltetrahydrofolate (NOT 5,10
methyleneTHF). Note: the methenyl variant (often confused; for example the heartfixer.com and Yasko diagrams have it wrong) goes on to make thymidine via thymidine synthetase and dUMP. People with Smith-Magenis disease are missing SHMT1 entirely (like a knockout mouse) but still have 50% SHMT activity because SHMT2 is partially redundant if needed.
That is known. Now what is hazy or is speculative is another thing entirely.
Hypothetically, I could imagine a scenario where a pile-up in folinic acid down-regulates SHMT1 & maybe SHMT2 (a big IF that I am not certain of at present). This could then potentially start choking the input to MTHFR. For a regular person this probably doesn't arise as folinic acid never rises above some level and can be managed with some sort of alacrity. I think this is where Rich (and others) thought MTHFS comes into play. I still think this is hypothetical.
I will admit I am still in the process of studying SHMT. The SHMT1 C1420T SNP listed by Yasko et al is pretty conclusively now shown to NOT be the only “player” as it by itself does NOT lower or raise enzyme activity. But it does appear from correlations in older studies with other indications that it may be part of a fragile haplotype where some other mutations we do not know about makes things go askew and enzyme activity drops. There is a lot of confusion about SHMT1 SNPs and their significance. No one really knows.
For example:
http://journals.lww.com/psychgeneti...ations_in_folate_metabolic_pathway_and.2.aspx
Note how the non-autistic children have more of the “risk” A allele and the thinking is A is protective vs autism. Yet SHMT is a cornerstone mutation of the Yasko protocol with first priority. Eh?
Yet SHMT activity IS important:
http://ajcn.nutrition.org/content/93/4/789.full
But here -/- means literally no gene as in deletion. Not the same as a single SNP C1420T.
The exact balancing act between SHMT1 and SHMT2 is complicated further by that SHMT2 encodes its own variant of SHMT1 if necessary for expression. i.e. redundancy. Like I said complicated.
In her book Autism Pathways to Recovery Chapter 6, Dr Yasko says:
“Supplementing with nucleotides, which are a form of our DNA bases, can help to both support thymidine, while maintaining appropriate methylation cycle activity. In addition, both iron and a form of folate called “5 formyl THF ” help to regulate SHMT activity. That’s why using lactoferrin (which helps to control iron levels) along with low doses of 5 formyl THF (found in the product, ActiFolate) help shift methylation activity back to the short and long routes around the cycle.”
So autistic kids who in reality tend to have the wild type ‘G’ allele as we saw conclusively above, are viewed as having too much ‘diversion’ from methylation by thymidine synthase or is it just too little production of both? Not clear to me by that paragraph. The folinic acid “regulates” SHMT. Up or down? We assume in reality ‘down’ by negative feedback. But SHMT1 and SHMT2 or only SHMT1? Yet even worse the folinic acid and nucleotides, etc. are being presumably given to patients with the A ‘risk’ allele. Again, eh? (Note the MTHFR c677T and MTHFR A1298C haplotype is very loaded towards autism as an aside).
But ignoring that, let us say regardless of SNPs, a person really has a down regulated, poorly functioning SHMT1 then a natural conclusion would be to supplement the end products of that enzyme. Right?
Supplementing methylfolate, whether SHMT2 is down regulated or not, is not an issue if we are tackling MTHFR after all. The folinic acid would be in principle be a back channel to the "warehouse" to help the dUMP and other cycles. THF will spin back from methylfolate if not in a methyl trap.
But … at what dose does supplementing folinic acid do only the “good” things listed above vs. suddenly start to further down-regulate already anemic SHMT1 production? Does SHMT2 re-balance to fit the bill or is it squashed. Can cytosolic folinic acid even cross into the mitochondria? Or is it all regulation at a transcriptional level?
However, I cannot at present imagine that large doses of folinic acid serve these purposes well. That seems more about flooding the folate cycle and hoping everything shakes out. If you will forgive me, seems more like a bit of using blunt forced trauma on the patient at high enough doses. But low doses may be a different story having more to do with augmenting DNA production and purine synthesis than boosting methylation capacity. Maybe that is for the 81%. The 19% may be kind of screwed for lack of a better term.
Personally I am staring a SHMT1 C1420T homozygote SNP in the face. But right now I am pretty sure I have not much of a clue what that really means. It puts me at risk (risk only) for impaired SHMT1 activity. But from what I have researched, in no way guarantees that. And like I said some of the existing information how it interacts as per autism, methylation, etc. is very suspect. I suppose I am not surprised after the researching the whole VDR SNP notational debacle. At some point I will try to post a SHMT thread, but there are like 15 papers lurking on the topic and I really can’t find a direct definitive connection for some of the stuff regarding the tested SNP.
Anyways I have a bad head cold and am going to try and get some sleep.