Overdriving the methylation cycle, elevated sarcosine and prostate cancer
Hi, all.
I just learned something that I think I should pass on to you.
As you know, I have expressed concern in the past about the possibility that high dosages of 5-methyl THF together with high dosages of methyl B12 could overdrive the methylation cycle in people with CFS.
I have now received plasma amino acids test results from two people who have been on this type of protocol for some time (names withheld because of patient privacy rights), and this is the pattern they have both shown:
1. MethionineHigh
2. HomocystineBelow detection limit
3. Methionine sulfoxide--Detectable to elevated
3. SarcosineVery high
4. Serine/Glycine ratio--Low
5. CystathionineBelow detection limit
6. TaurineLow-normal
This is how I interpret this pattern:
The high methionine level is unusual in CFS, as it is usually low. This suggests that it is being recycled rapidly from homocysteine, unless it is being supplemented.
The undetectable homocystine, which is the oxidized form of homocysteine, suggests that homocysteine is also very low. This inference can be made because the presence of methionine sulfoxide gives evidence of a state of oxidative stress, which suggests that if homocysteine were present in significant amounts, homocystine would also be detected.
The combination of inferred low homocysteine and high methionine suggests that the conversion of homocysteine to methionine is rapid, thus inferring that the methylation cycle is running faster than normal.
The very high sarcosine confirms that the methylation cycle is running faster than normal. The formation of sarcosine from glycine by the enzyme glycine N-methyl transferase serves as sort of a pressure relief valve for the methyation cycle, dissipating methylation capacity by forming sarcosine when the ratio of S-adenosylmethionine to S-adenosylhomocysteine is tending to become too high.
The low ratio of serine to glycine suggests that the serine hydroxymethyltransferase (SHMT) reaction is running faster than normal, which suggests that tetrahydrofolate is higher than normal, which in turn suggests that the methionine synthase reaction is running faster than normal.
If the methionine synthase reaction is running faster than normal, the cystathionine beta synthase reaction would not be expected to be able to compete as well as normal for homocysteine, and thus the flow down the transsulfuration pathway would be expected to be lower than normal. Evidence that this true is the undetectable level of cystathionine.
Additional support for low flow down the transsulfuration pathway comes from the low-normal level of taurine.
What would be the consequences of overdriving the methylation cycle?
I think that one would be that the sulfur metabolism, including cysteine, glutathione and taurine would not be able to recover as rapidly as they would if the methylation cycle was not running so fast. This could slow the overall recovery, I think. It would leave the person in a state of oxidative stress longer, and would slow the recovery of the detox system and the immune system, as well as maintaining the symptoms caused by low glutathione for a longer time.
The other consequence is that sarcosine remains high in an effort to control the SAMe to SAH ratio, which is being pushed higher than normal. Does this matter?
It looks as though it might, from a paper published last year, abstracted below (the full paper is available from PubMed, by entering the PMID number in their search box, and then clicking on the colored box at the upper right of the abstract page.) Note especially the paragraph that begins with the word "sarcosine":
Nature. 2009 Feb 12;457(7231):910-4.
Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM.
The Michigan Center for Translational Pathology, Ann Arbor, USA.
Comment in:
* Nature. 2009 Feb 12;457(7231):799-800.
Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease.
Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells.
Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
PMID: 19212411 [PubMed - indexed for MEDLINE]
I think this is something to be concerned about. In particular, I think it would be wise for any men who have been on this protocol for an extended time to have a digital rectal exam and a PSA test to check for prostate cancer. If prostate cancer is present, I think it would be wise to lower these dosages to allow sarcosine to come down.
Beyond that, I continue to have doubts about the advisability of use of this high dosage protocol. If sarcosine stimulates prostate cancer, it might stimulate other types of cancer as well. I continue to believe that people should proceed more slowly with treatment, and should monitor the status of their methylation cycle by lab testing during the treatment, aiming to restore it to normal status, rather than to overdriven status.
Best regards,
Rich
Hi, all.
I just learned something that I think I should pass on to you.
As you know, I have expressed concern in the past about the possibility that high dosages of 5-methyl THF together with high dosages of methyl B12 could overdrive the methylation cycle in people with CFS.
I have now received plasma amino acids test results from two people who have been on this type of protocol for some time (names withheld because of patient privacy rights), and this is the pattern they have both shown:
1. MethionineHigh
2. HomocystineBelow detection limit
3. Methionine sulfoxide--Detectable to elevated
3. SarcosineVery high
4. Serine/Glycine ratio--Low
5. CystathionineBelow detection limit
6. TaurineLow-normal
This is how I interpret this pattern:
The high methionine level is unusual in CFS, as it is usually low. This suggests that it is being recycled rapidly from homocysteine, unless it is being supplemented.
The undetectable homocystine, which is the oxidized form of homocysteine, suggests that homocysteine is also very low. This inference can be made because the presence of methionine sulfoxide gives evidence of a state of oxidative stress, which suggests that if homocysteine were present in significant amounts, homocystine would also be detected.
The combination of inferred low homocysteine and high methionine suggests that the conversion of homocysteine to methionine is rapid, thus inferring that the methylation cycle is running faster than normal.
The very high sarcosine confirms that the methylation cycle is running faster than normal. The formation of sarcosine from glycine by the enzyme glycine N-methyl transferase serves as sort of a pressure relief valve for the methyation cycle, dissipating methylation capacity by forming sarcosine when the ratio of S-adenosylmethionine to S-adenosylhomocysteine is tending to become too high.
The low ratio of serine to glycine suggests that the serine hydroxymethyltransferase (SHMT) reaction is running faster than normal, which suggests that tetrahydrofolate is higher than normal, which in turn suggests that the methionine synthase reaction is running faster than normal.
If the methionine synthase reaction is running faster than normal, the cystathionine beta synthase reaction would not be expected to be able to compete as well as normal for homocysteine, and thus the flow down the transsulfuration pathway would be expected to be lower than normal. Evidence that this true is the undetectable level of cystathionine.
Additional support for low flow down the transsulfuration pathway comes from the low-normal level of taurine.
What would be the consequences of overdriving the methylation cycle?
I think that one would be that the sulfur metabolism, including cysteine, glutathione and taurine would not be able to recover as rapidly as they would if the methylation cycle was not running so fast. This could slow the overall recovery, I think. It would leave the person in a state of oxidative stress longer, and would slow the recovery of the detox system and the immune system, as well as maintaining the symptoms caused by low glutathione for a longer time.
The other consequence is that sarcosine remains high in an effort to control the SAMe to SAH ratio, which is being pushed higher than normal. Does this matter?
It looks as though it might, from a paper published last year, abstracted below (the full paper is available from PubMed, by entering the PMID number in their search box, and then clicking on the colored box at the upper right of the abstract page.) Note especially the paragraph that begins with the word "sarcosine":
Nature. 2009 Feb 12;457(7231):910-4.
Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.
Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM.
The Michigan Center for Translational Pathology, Ann Arbor, USA.
Comment in:
* Nature. 2009 Feb 12;457(7231):799-800.
Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease.
Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells.
Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
PMID: 19212411 [PubMed - indexed for MEDLINE]
I think this is something to be concerned about. In particular, I think it would be wise for any men who have been on this protocol for an extended time to have a digital rectal exam and a PSA test to check for prostate cancer. If prostate cancer is present, I think it would be wise to lower these dosages to allow sarcosine to come down.
Beyond that, I continue to have doubts about the advisability of use of this high dosage protocol. If sarcosine stimulates prostate cancer, it might stimulate other types of cancer as well. I continue to believe that people should proceed more slowly with treatment, and should monitor the status of their methylation cycle by lab testing during the treatment, aiming to restore it to normal status, rather than to overdriven status.
Best regards,
Rich
