I honestly do not have any idea of where to start with this. I have so much info and have done so many things with my studies here, its difficult for me to go back to the beginning. I began looking at this SNP as there really is very little information about it. I have also been mucking around with arginine lately, as recommended by my toxicologist years ago. Back then I did not have methylation in place, and I certainly didn't have any reaction to it like I do now. I have read posts here mentioning arginine, and the reactivation of viruses, but honestly, I haven't had that. In fact, I have had some startling reactions in my cognitive function, energy, and .....my skin. Yeah, I know....weird. At least I thought so until I started looking at SHMT more closely. So forgive me, I will just jump in and take the plunge.
Please, by no means, if you do not have this SNP, there are other implications when this pathway is strained despite mutation or not. If you do have this mutation, it is a down regulation of its function and besides the MTHFR mutation, will also lead to insufficient THF. A situation in which this pathway may be strained is glycine based detoxification, upregulated to exposure, in which places a strain on the serine hydroxymethyltransferase enzyme pathway. It is this pathway that is mainly responsible for glycine biosynthesis. It is also this pathway that leads to pyruvate, so again, bear with me through all this information.
As a side note, you ever wonder why Dr. Yasko puts SHMT first of the first priority mutations? I did, but couldn't find her reasoning, at least not specific enough for me. I now have my own, and I offer to you all in the hopes it will help someone else.
Her definition goes like this....SHMT shifts methylation away from the long and short routes and goes into a side reaction that leads to thymidine production. The thiamine discussion taking place right now pertains also to this enzyme pathway. The long and short routes are those of the folate pathway.
There are two isoforms of SHMT, 1) cSHMT, and 2) mSHMT. cSHMT is found in the cytosol, of which the 1420CC genotype can equate to higher Hcy levels and significantly lower RBC and plasma folate levels. Imagine combining this one with a MTHFR mutation? The CT genotype is associated with a shift in the distribution of folate derivatives. Specifically what shift has yet to be elucidated to me. mSHMT is found in the mitochondria.
Onwards...
SHMT is a member of the PLP or P5P (B6) enzyme class. P5P is needed by both mSHMT and cSHMT at all times to activate this enzyme. Upregulation would then lead to low levels of B6 for the many other umpteen reactions in the body, and could also be considered a contributor to low levels being found in some. I think this enzyme would be first priority because of its function, so diversion of cofactors would keep this running, eventually lower levels of cofactors ensue, and the SHMT will become strained amongst others. A downregulation mutation leading to some significant problems.
Its functions more specifically....SHMT uses serine to synthesize glycine. P5P is a cofactor in certain enzymes that deal with transamination reactions required for the synthesis and catabolization of amino acids (AA). I place heavy emphasis on catabolism here.
Transamination reactions are the process in which an AA and an alpha-keto acid react. In this process the amino groups are removed from the AA, leaving an alpha-keto acid. This alpha-keto acid is then converted by numerous co-factors including P5P, into the corresponding AA in protein chains. This is potentially huge for us, as so many of us experience the catabolic state.
More functions...and probably one of the most important. SHMT is essential for the acquisition of one carbon units for subsequent transfer reactions. 5, 10 methyleneTHF is used by thiamidate synthase to convert dUMP to dTMP.
Many diseases are currently thought to be linked to the improper or lack of function of the SHMT function. Why don't we hear much about this? This pathway has many implications in the ME/CFS circles, mutation or not. I digress...
Back to dUMP and dTMP. What they are currently finding is that the incorporation of dUMP into DNA instead of the preferred dTMP, is that dUMP results in DNA strand breaks because dUMP is not being methylated to dTMP.
This effect has been shown to be present in patients with Leukemia whose DNA does not repair itself and causes deletions in DNA segments and also the translocation of chromosomes. Although our condition is not Leukemia by any means, I used it as an example because so many of the effects I have experienced with ME/CFS have been quite similar, and that this effect is quite possible with those diseases being correlated to SHMT.
Back to catabolism. This concept is related to ATP, all of which we are all too familar with, but I rarely see it said as to why, chemically. Why dont we have any energy? Why are some losing body mass, muscle wasting. SHMT leads to pyruvate of which then leads to the citric acid cycle. Little SHMT, little energy. We lose muscle mass in the catabolic state and we can't recover from it because we dont have the proper DNA to heal the damage. Catecholamines, infections, stress/trauma, and cytokines are the main contributors to the catabolic state. Food for thought anyways.
Anyone lose their sense of taste when they got this? Incidently, ATP is associated with the ability to taste?
So if the transmination process is compromised, we then lack the ability to break down amino acids to be incorporated into proteins, so we lack functional proteins and of which we then see a need to increase protein intake due to the catabolic state. But the intake from diet isn't enough, or is just enough to get us through a resting state, anything more and we go into a more severe catabolic state in which we cannot recover from the extra activity.
Going to watch the fireworks.....finish later with an edit.
LaurieL
Please, by no means, if you do not have this SNP, there are other implications when this pathway is strained despite mutation or not. If you do have this mutation, it is a down regulation of its function and besides the MTHFR mutation, will also lead to insufficient THF. A situation in which this pathway may be strained is glycine based detoxification, upregulated to exposure, in which places a strain on the serine hydroxymethyltransferase enzyme pathway. It is this pathway that is mainly responsible for glycine biosynthesis. It is also this pathway that leads to pyruvate, so again, bear with me through all this information.
As a side note, you ever wonder why Dr. Yasko puts SHMT first of the first priority mutations? I did, but couldn't find her reasoning, at least not specific enough for me. I now have my own, and I offer to you all in the hopes it will help someone else.
Her definition goes like this....SHMT shifts methylation away from the long and short routes and goes into a side reaction that leads to thymidine production. The thiamine discussion taking place right now pertains also to this enzyme pathway. The long and short routes are those of the folate pathway.
There are two isoforms of SHMT, 1) cSHMT, and 2) mSHMT. cSHMT is found in the cytosol, of which the 1420CC genotype can equate to higher Hcy levels and significantly lower RBC and plasma folate levels. Imagine combining this one with a MTHFR mutation? The CT genotype is associated with a shift in the distribution of folate derivatives. Specifically what shift has yet to be elucidated to me. mSHMT is found in the mitochondria.
Onwards...
SHMT is a member of the PLP or P5P (B6) enzyme class. P5P is needed by both mSHMT and cSHMT at all times to activate this enzyme. Upregulation would then lead to low levels of B6 for the many other umpteen reactions in the body, and could also be considered a contributor to low levels being found in some. I think this enzyme would be first priority because of its function, so diversion of cofactors would keep this running, eventually lower levels of cofactors ensue, and the SHMT will become strained amongst others. A downregulation mutation leading to some significant problems.
Its functions more specifically....SHMT uses serine to synthesize glycine. P5P is a cofactor in certain enzymes that deal with transamination reactions required for the synthesis and catabolization of amino acids (AA). I place heavy emphasis on catabolism here.
Transamination reactions are the process in which an AA and an alpha-keto acid react. In this process the amino groups are removed from the AA, leaving an alpha-keto acid. This alpha-keto acid is then converted by numerous co-factors including P5P, into the corresponding AA in protein chains. This is potentially huge for us, as so many of us experience the catabolic state.
More functions...and probably one of the most important. SHMT is essential for the acquisition of one carbon units for subsequent transfer reactions. 5, 10 methyleneTHF is used by thiamidate synthase to convert dUMP to dTMP.
Many diseases are currently thought to be linked to the improper or lack of function of the SHMT function. Why don't we hear much about this? This pathway has many implications in the ME/CFS circles, mutation or not. I digress...
Back to dUMP and dTMP. What they are currently finding is that the incorporation of dUMP into DNA instead of the preferred dTMP, is that dUMP results in DNA strand breaks because dUMP is not being methylated to dTMP.
This effect has been shown to be present in patients with Leukemia whose DNA does not repair itself and causes deletions in DNA segments and also the translocation of chromosomes. Although our condition is not Leukemia by any means, I used it as an example because so many of the effects I have experienced with ME/CFS have been quite similar, and that this effect is quite possible with those diseases being correlated to SHMT.
Back to catabolism. This concept is related to ATP, all of which we are all too familar with, but I rarely see it said as to why, chemically. Why dont we have any energy? Why are some losing body mass, muscle wasting. SHMT leads to pyruvate of which then leads to the citric acid cycle. Little SHMT, little energy. We lose muscle mass in the catabolic state and we can't recover from it because we dont have the proper DNA to heal the damage. Catecholamines, infections, stress/trauma, and cytokines are the main contributors to the catabolic state. Food for thought anyways.
Anyone lose their sense of taste when they got this? Incidently, ATP is associated with the ability to taste?
So if the transmination process is compromised, we then lack the ability to break down amino acids to be incorporated into proteins, so we lack functional proteins and of which we then see a need to increase protein intake due to the catabolic state. But the intake from diet isn't enough, or is just enough to get us through a resting state, anything more and we go into a more severe catabolic state in which we cannot recover from the extra activity.
Going to watch the fireworks.....finish later with an edit.
LaurieL