Yasko has three first priority mutations, 1) SHMT, 2) ACAT, and 3) CBS. I have hetero mutations in all three as an aside.
I believe the connection of ACAT and adenosylcobalamin lies in the final steps of cobalamin synthesis. The propanol side chain and the nucleotide loop that links to the corrin ring. Those with ACAT mutations are also highly correlated with chronic dysbiosis. Something I constantly have to address. I think its this dysbiosis, and either the interference of the synthesis of adenosylcobalamin, or the lack of the bacteria in which are known to produce it, or finally, an overgrowth of bacteria in which steal it.
Sorry I should have clarified: I meant I don't see the connection to needing 8.6 grams of adb12 and your heterozygote ACAT mutation in my earlier post.
I have seen the heartfixer and read Yasko's treatment book and seen some of her online presentations so I understand she has a careful queue priority for treatment.
I too have chronic dysbiosis but am unaware of any ACAT mutation so while I am not sure the correlation is bi-directional. Gut dysbiosis is quite the menagerie of problems.
You might ask why a heterozygous ACAT can not by itself be the problem ... well my hypothesis is based on statistics. The same holds for SHMT.
Basically far too many people are heterozygous for ACAT or SHMT.
Here is an web site with the observed frequency of ACAT1 rs3741049 SNP (I think this is one Yasko tests).
http://browser.1000genomes.org/Homo...08010427;v=rs3741049;vdb=variation;vf=2818389
Note the AG genotype for the first row for ALL (not race specific) is a whopping 24.2. Even the AA homozygote is >4%.
As a physicist turned bioinfomaticist, that the 24% number is WAY too high to support a severe problem which would then be afflicting large chunks of the population. Hence I would not think a heterozygote for ACAT would be so detrimental if looked at in isolation.
So I still don't see the connection to ACAT ... though the clinical benefits for you are clear. Can't argue with that
Now for the SHMT SNP (rs1979277).
The data for that is here:
http://browser.1000genomes.org/Homo...18232596;v=rs1979277;vdb=variation;vf=1551359
Now the AG heterozygous genotype is even higher at 33%!
So the odds of a heterozygous individual for both SHMT and ACAT is about 8%. At 1 in 12 people roughly that is still
a really large number. Contrast that with someone who is homozygote in both mutations and now you are talking something closer to 0.3%.
I understand Dr Yasko places these SNPs at high importance in her treatment protocol but she does not do a good job at all imo in her nutrigenomics protocol of distinguishing heterozygote from homozygote in terms of phenotype impact and in genomics that is a HUGE deal. Let's remember she started her protocol with children with autism who probably really are homozygote in one, two or more key SNPs. Even then things can be murky due to all the complexity.
Incidently, ad b12 also affects nucleotide assembly. Which is where the SHMT being partially functional could add to my problems, and why so many with ACAT mutations are recommended to supplement nucleotides. Certain bacteria's are known to steal nucleotides for there own use or their metabolites interfere with our own production.
I believe ACAT interferes with those steps above, and two involve the formation of adenosylcobalamin and then the activation of adenosylcobalamin. What do you think? I am not an expert in this particular area.
Do you have a source for the nucleotide direct synthesis link?
The reason I ask is I know adb2 is directly involved in the synthesis of deoxyribonucleotides (as an intermediate to DNA nucleotides) via class 2 ribonucleotide reductase and 5'deoxy-adb12 but that class is only for bacteria to my knowledge. Eukaryotes use class 1a which uses iron.
But maybe I am missing something
To add....ACAT mutations can result in B12 deficiencies as can a few other mutations. Considering my responses to both forms of active B12, I would say there is something wrong in my adenosylcobalamin side. Whether it be the formation of, or the activation of, I have not been able to determine as of yet.
Fair enough but again you are heterozygous for ACAT so not sure how that explains it. But I understand what you are saying about the importance of both active forms of B12 (mb12 and abd12) to you ... would just love to know why!
It is interesting that you would ask, as these were supportives I found incredibly beneficial prior to my methylation attempts and already had on board when I started. I had to up my B2 in response to inappropriate proteins. I have taken ALA off and on as well. I am currently low dose. Interestingly enough the herbs I found to help control NFkappaB to be queceritin and turmeric a derivative of curcumin, also found beneficial in ACAT mutations.
Remember that the key step to convert the methylene intermediate into 5MTHF is catalyzes by riboflavin-5-phosphate so maybe B2 helped you in other ways as well.
Quercetin and turmeric are very important as anti-inflammatory agents. If you have read this thread:
http://forums.phoenixrising.me/inde...min-the-very-large-gorilla-in-the-room.20229/
you will see there is a link of BH4 and adb12 to lowering inflammation. It was hypothesized that this involves NO
and its other variants being better modulated. Ironically this suggests that for people with lower BH4 due
to ammonia issues (CBSers) or people with MTHFR A1298C (like myself) that there may be further compromising
of BH4 status if adb12 is supplied. But I am not sure it may be BH4 for some that is the rate limiting agent. Not clear.
Ironically for me on prednisone and medrol, use of quercetin gives me insomnia since it also slows down COMT
catabolism while maybe over-lowering inflammation = no sleep!
As far as the hetero status, I haven't heard of anyone being homozygous, as that would be fatal, early on, manifesting as MMA aciduria. A death sentence if not caught. I am not an expert, and sure would like some input. I like to group think.
Have to disagree there. According the data I linked 4.4% of the population is homozygote. That would be the leading cause of mortality in infants / children in the developed world. I am sure it is bad but it suggest homoygote in ACAT1-02 still has some activity.
-------------------------
On a separate note remember though that 8.6 grams is not what is absorbed sublingually regardless how long one keeps it under their upper lip. Though based on other forum posts if absorption is an issue, supposedly other posters claim the Anabol diboceplex adb12 works much better than Source Naturals.
Thought provoking discussion topics you raised though. Most fun on a reply I have had yet. You made me work my bioinformatics "muscles". Thanks