The Methionine Cycle

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The methionine cycle is the second key process that works alongside the folate cycle to produce SAMe (S-Adenosyl-Methionine), driving methylation.


The two cycles are linked via an important enzyme called methionine synthase (aka 5-methyltetrahydrofolate-homocysteine methyltransferase or MTR, for short!). MTR takes the methyl group from the methyl folate produced at the end of the folate cycle and transfers it onto cobalamin (vitamin B12). The result is methyl B12, which is then used to re-methylate homocysteine, converting it to methionine, then to SAMe. The remaining un-methylated folate is recycled back into the folate cycle as THF. SNPs in MTR slow down this process and can be supported by optimising dietary or supplemented vitamin B12 (especially methyl B12) and zinc as a cofactor.

Let's just reflect on this basic process. Essentially folate plus B12 makes SAMe. Of course, it is more complicated, with other cofactors involved, but that is the foundation. These 2 nutrients are the heart of the process and interdependent So if one is imbalanced, it may cause an excess of the other. For example, insufficient B12 may result in methyl folate not being able to give up its methyl group and it gets stuck in-between the two cycles, with MTR not being able to do its part. The is called the folate trap, and, as well as slowing down production of SAMe, it will also stop THF going back into the folate cycle, affecting folate levels.


The B12 used by MTR eventually becomes oxidised, and needs to be reactivated via methylation by another enzyme  -  MTRR (Methionine synthase reductase), using SAMe as a methyl donor. MTRR activity can also be significantly impacted by heavy metals (including mercury) and nitrous oxide (in anaesthetics and laughing gas), reducing availability of methyl B12.  Support is as per MTR by optimising dietary or supplemented vitamin B12 (especially methyl B12) and zinc as a cofactor. Also reduce heavy metal toxicity and support methylation in general to promote SAMe.

B12 Supply - FUT2 & TCN2

Supply of B12 to MTR and MTRR could, of course, be impacted by dietary levels (vegan), pernicious anaemia, poor digestion, low levels of stomach acid, and medications like antacids or PPIs. Another gene/SNP comes into play here. FUT2 regulates expression of H antigens on the gastrointestinal mucosa and a FUT2 ‘secretor type’ has increased risk of H. pylori infection and gastritis, potentially reducing B12 absorption. Support should involve reducing any gastritis and H pylori levels and bypassing the enteric route for B12 absorption by using sublingual B12 or injections.

Supply may also be affected by transport of B12 - SNPs in TCN2 (transcobalamin II) gene, which binds and transports B12 from the intestine into blood and then to cells. This could reduce B12 levels even when diet and digestion are optimal. Support, again, involves optimising vitamin B12 levels


Methionine is then converted to SAMe via the MAT1A enzyme (methionine adenosyltransferase). SNPs may downregulate activity and lower the rate of SAMe synthesis, impacting methylation. Support with the cofactors magnesium and ATP (by supporting mitochondrial energy production). You could also consider a SAMe supplement, but bear in mind it is a medicine in some countries, and there is some evidence that it can imbalance the system and downregulate endogenous SAMe synthesis. It is always much better to address the underlying causes, and support the other parts of the cycles to work more effectively.

Once SAMe has given up its methyl group, it is converted to S-Adenosyl-Homocysteine (SAH). AHCY (Adenosylhomocysteinase) then converts SAH to adenosine and homocysteine. This reaction is reversible and can adapt to higher levels of homocysteine, converting it back to SAH. Sometimes this may make homocysteine levels look normal on testing, despite issues with methylation. Testing for the ratio of SAH compared to SAMe, where SAH is higher, can give a better idea of this issue. Any log-jam caused either by high SAH or by homocysteine can slow down SAMe synthesis (via negative feedback). 


There is also an alternative 'short cut' route for conversion of homocysteine to methionine - via the BHMT (betaine-homocysteine S-methyltransferase) enzyme. Rather than using vitamin B12, it is dependent on a substance called betaine (aka trimethylglycine), which is rich in methyl groups. SNPs in BHMT can be supported by increasing TMG-rich foods (beets, broccoli, quinoa, shellfish, spinach, and algae) or supplements, or choline, which can be converted to betaine. 

Choline can be supplied from diet, or made in the body as phosphatidyl choline via the PEMT enzyme There can be SNPS in PEMT, reducing activity, or it may be depleted by reduced methylation as it is SAMe-dependent. Choline dehydrogenase (CHDH) then oxidises choline from these sources to betaine. CHDH SNPs lower activity, with impacts on cell membrane, mitochondrial structure, sperm concentration and motility, foetal development, and increasing risk of NAFLD (as choline is a key constituent of bile). Support with dietary or supplemented choline and optimise methylation for PEMT. CHDC can also be supported by Vitamin B2 and PQQ (pyrroloquinoline quinone) found in kiwi fruit.

So, via the folate and methionine cycles working together, the potentially negative metabolite homocysteine is recycled to produce a new supply of SAMe, promoting methylation. However, some homocysteine is used in the Transulphuration pathway to make other useful substances like glutathione.

Read all about the Transulphuration Pathway next.

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