I agree with you SonjaS, I wish I hadn't chimed in on this one either. You are rehashing stuff I have long since learned about and walked away from so I didn't have my sources all lined up to withstand scrutiny. Two issues here, firstly, I mistook the role of VDR and methyl b 12 since it appears to be more of an indirect role with MTR. It looks like MTR/MTRR leads to what we all know about.....Methionine, SAM, and SAMe and its really about methyl donors and dopamine levels.
Second, you have more faith in science then I do. I used to believe all that too but then I had a friend who worked in the industry "cleaning" up study findings and as an ICU nurse, I got to see all the patients they dumped out of our studies when they suddenly didn't "fit the criteria" when it was really about not falling in line with what the researchers wanted. Not to mention the fact that way too many peer reviewed nutritional studies are never printed because the medical bodies won't do it. Don't get me wrong, I'm the first person to jump on a study that supports something I already believe. I LOVE quoting "scientific data" that supports my position.
But in reality, it takes alotta $$$ and precious, precious time to conduct a study and even more to include more then a few variables so the idea about it being a scientist's duty to get their results in print is sorta laughable. In fact, it was this very point that saved my life.....indirectly. My doc met Rich at a UC Davis MIND meeting because she called out Jill James on such a bogus statement. When she was finished, Rich said he wanted her to have a standing ovation but he settled for talking to her half the night about science and medicine. This was how my doc learned about Yasko. Anyway, I love your enthusiasm and idealism.....if only it translated to the medical and scientific field (when there aren't billion dollar drugs on the line). As for biochem being hard science, well, it is and it isn't. Take glutathione. Up until Rich's passing (God bless that man!) he and Yasko and Pall all agreed that this was a problem but which comes first and why? And everyone used to think you had to replace glutathione but no matter how much they did, people didn't stay better. The basic tenets may be somewhat predictable but all the rest isn't. And all the rest is where healing people comes into play. This is where the clinician plays such a big part because they see how patients respond even while the scientists are tellng them it should work. This is usually mocked as "soft science" or "empirical" data but it is what it is. I know the answer isn't to throw the scientist's observations out so I guess we need both. But maybe we need to respect the outcomes as much as the test results?
The stuff below is an old esoteric snippet from some of Yasko's earliest comments. I'm sure some stuff has changed but I thought I should provide what she said and not my memory of it.
MTR : methionine synthase MTRR : methionine synthase reductase
Methionine synthase is responsible for the conversion of homocysteine back to methionine. A number of mutations that actually decrease the activity of this enzyme have been well characterized. Mutations that increase the activity have also been described for this gene. The A2756G mutation in the methionine synthase gene (MTR) has been reported to increase the activity of this enzyme.
MTR A2756G
As is the case for the CBS C699T up regulation, the ultimate result of a number of these mutations that increase rather than decrease enzymatic activity is to deplete the methylation cycle of key intermediates that are needed for this pathway to function properly. In the case of the MTR A2756G, the net result of this upregulation may be to use up B12 at an even faster rate than normal, causing a depletion of methyl B12 from the cycle.
Decreased function of the MTR or a lack of B12 will diminish the level of conversion of homocysteine to methionine via this enzymatic route. A secondary route exists to convert homocysteine to methionine, utilizing the BHMT enzyme. Rather than using 5 methyl tetrahydrofolate and methyl B12 for this conversion, the BHMT enzyme utilizes TMG (betaine) as starting material for this alternative reaction. As described in the PDR (Physicians Desk Reference) "Betaine or trimethylglycine is a quarternary ammonium compound that was first discovered in the juice of sugar beets
(Beta vulgaris). Betaine is a metabolite of choline and is a substrate in one of the two recycling pathways that convert homocysteine to L-methionine. The other and principal recycling reaction is catalyzed by the enzyme methionine synthase and uses methylcobalamin as a cofactor and 5- methyltetrahydrofolate as a cosubstrate.”
Methionine synthase reductase (MTRR) acts in concert with methionine synthase enzyme to recycle homocysteine back to methionine. The function of methionine synthase reductase (MTRR) is to regenerate methyl B12 for methionine synthase to utilize. Mutations that impair the function of MTRR will have secondary consequences on the activity of the methionine synthase gene. Even if there are no mutations in the methionine synthase gene, the inability of MTRR to regenerate sufficient methyl B12 will impact upon MTR activity in the methylation cycle.
The combination of a mutation in MTRR that compromises it’s ability to regenerate B12, in concert with a MTR upregulation that is utilizing B12 at an accelerated rate would result in severely depleted levels of methyl B12 in the body. This would also create a roadblock in the methylation pathway between methionine and homocysteine that would require nutritional bypass for restored pathway function.
COMT : catechol O methyl transferase VDR : vitamin D receptor
If an individual has a COMT variation it means that they have a change in one of the amino acids of the enzyme. In the case of COMT one of the frequent amino acid changes is from a valine to a methionine. This is what is being tested for when the COMT V158M SNP test is run. The lab is able to look at the DNA to determine the information for which of these two amino acids that your copy of COMT contains. If you have the version with the information for a methionine in the sequence, it is written as COMT + meaning that you are positive for the methionine version. If you are COMT- it means that you do
not have methionine in that spot of the enzyme and you have valine there instead. Since the valine in that spot is considered the “norm” the methionine represents the variation, so it is + for a variation being present.
The form of the COMT with the variation (the methionine in it at a particular location) is a less efficient form of the enzyme. When the methionine is present it does not do as good a job of breaking down the dopamine. Therefore an individual who is COMT+ will not break dopamine down as easily. An individual who is COMT- (with the valine in that spot) will break dopamine down more efficiently.
The COMT enzyme uses methyl groups to help to inactivate dopamine. “COMT” stands for catechol O methyl transferase. So that when the COMT is working to inactivate dopamine and nor epinephrine it does so by using methyl groups that you have available in your system. These methyl groups are donated by SAMe that is generated via the methylation pathway. Individuals who have the less efficient form of COMT (the COMT+ +) will be using less methyl groups because they are not inactivating dopamine as rapidly. Relative to the COMT - - individual they will have more methyl groups available for other reactions in the body.
Clinically, I have found that both the COMT status, as well as the VDR Taq genes act in concert to have an impact upon overall need for methyl donors and dopamine support. In general individuals who are COMT - - will have lower levels of dopamine due to enhanced COMT activity and will need and are able to tolerate higher doses of methyl donors. Conversely individuals who are COMT + + will have increased levels of dopamine, due to less efficient breakdown, and need and tolerate lower amounts of methyl donors.
In addition, two of the three vitamin D receptor mutations also appear to play a role in dopamine levels and methyl donor tolerance. I believe that this is due to the relationship between vitamin D receptor and dopamine levels. Vitamin D increases the level of the enzyme involved in synthesizing dopamine. Increased levels of vitamin D would be expected to lead to increases in dopamine, norepinephrine and epinephrine. The VDR/Taq – genetic status results in higher levels of vitamin D. Therefore, individuals who are negative for the VDR Taq polymorphisms (VDR /Taq - -) may have higher levels of dopamine due to enhanced levels of vitamin D. As would be expected if this were the case, I have found that these individuals are more sensitive to nutritional supplementation with methyl donors and nutrients that enhance dopamine levels than individuals who are homozygous (have both copies) for the VDR /Taq + + variation.
Increased levels of dopamine appear to aid in
protecting cells from arsenic toxicity under conditions of low glutathione. This would suggest that supporting healthy dopamine levels for COMT – and VDR /Taq + individuals who also have glutathione mutations and/or CBS up regulations (which lead to decreased glutathione) may be helpful in reducing the effects of arsenic toxicity. Animal models indicate that chronic arsenic exposure leads to decreases in dopamine. Therefore low dopamine levels (in conjunction with reduced glutathione) create a “catch 22” whereby the toxicity of arsenic is increased, leading to further reductions in dopamine.
COMT-- VDR/Taq-- • MTR+or++
• MTRR +or++
There is also a mutation in the methionine synthase reductase gene (MS_MTRR or MSR), as well as a mutation in the methionine synthase gene (MS or MTR). The function of MSR is to regenerate B12 for the MS to utilize. The methionine synthase mutation is an up regulation mutation that enhances the activity of the enzyme. This should cause the enzyme to use up added B12 at an even faster rate than normal. What this means in practical terms is that he/she may be severely deficient in methyl B12. The supplementation of B12 is therefore very important for him/her. Due to his/her COMT and VDR /Taq status he/she should need and will tolerate the addition of methyl containing supplements. Supplementation with methyl B12 should be beneficial for him/her. This will both help to support the MTR mutation as well as to add methyl groups to his/her system.