Showing posts with label SAM. Show all posts
Showing posts with label SAM. Show all posts

Methylation and Vitamin U

 


Photo by Alonso Reyes on Unsplash


Previously we looked at the methionine cycle, one of the functions of which is to generate methylation capacity Vitamin U (S-methylmethionine) information: The methionine cycle and Vitamin U Here we'll take a closer look at methylation.

Methylation describes over 100 reactions in our body ranging from the biosynthesis of creatine and phosphatidylcholine to the methylation of cytosine residues of DNA. The universal methylation substrate is S-adenosylmethionine (SAM or SAMe), which is a form of methionine in which the methyl group has been activated and thus made suitable for transfer to acceptor molecules. Methylation is the transfer of a methyl group from a donor molecule to an acceptor molecule. Methylation capacity is maintained by the methionine cycle, which was covered previously.

The most renowned function of methylation is gene regulation, a component of epigenetics. Genes are made up of four nucleotides referred to using their initial - A,T,C,G. Methylation of particular C (cytosine) residues reduces expression of a particular gene by interfering with the binding of transcription factors involved in making the mRNA that encodes a protein. For example, the cell broadly methylates toxic genes like retroviruses that have been incorporated into our genome to silence them. When your methylation state is low, retroviruses can reactivate. Conversely, the promoters of genes that must be on at all times are usually embedded in CpG regions that are resistant to methylation.

Quantitatively, the most important methylation reaction in our body is the biosynthesis of creatine. Creatine is an amino acid used in our muscles to regenerate ATP, the major energy molecule in our body. Creatine is made in the liver from guanidinoacetate in a reaction catalyzed by guanidinoacetate methyltransferase (GAMT). This one reaction alone consumes 40-75% of our methylation capacity. Creatine travels from the liver to the muscles where it is activated by phosphorylation to produce creatine phosphate. The high-energy phosphate bond in creatine phosphate is used to regenerate ATP from ADP. The reason so much methylation capacity goes into making creatine is not just because creatine is vital, but rather that 1-3% of creatine cyclizes to form creatinine, which cannot be phosphorylated and is excreted as waste.  

Another major methylation reaction is involved in the biosynthesis of phosphatidylcholines. Although most phosphatidylcholines are made elsewhere, a significant portion is made by methylation of phosphatidylethanolamine. The enzyme phosphatidylethanolamine methyl transferase (PEMT) catalyses the transfer of three methyl groups from three SAM molecules in three consecutive steps to a single phosphatidylethanolamine molecule to produce a single molecule of phosphatidylcholine. Or said another way, phosphatidylcholine is trimethylated phosphatidylethanolamine.

Our methylation status can affect the ability to perform these functions. When the concentration of SAM is low, methylation slows down. The most common reason for a lack of methylation is insufficient methyl capacity from the diet. SAM is a reactive molecule that isn't stored in food or in our body. SAM supplements do exist, though they are relatively expensive, unstable and short-acting. The best way to meet our SAM requirements is by eating food containing nutrients that are used by our body to synthesize SAM. Our body makes SAM from methionine and ATP, with methionine supplying the methyl group. After SAM has donated its methyl group, we are left with S-adenosylhomocysteine, which in turn, is hydrolyzed to homocysteine. Homocysteine sits at an important metabolic fork. When our body is in a low methylation state, there is a tendency for homocysteine to be converted back into methionine by remethylation, even when the body may also be short of transsulfuration products such as glutathione. In contrast, when the methylation state in our body is normal, excess homocysteine is diverted into the transsulfuration pathway to form cysteine and its derivatives like glutathione and taurine.

Methionine is an essential amino acid found in protein. When methionine is remade from homocysteine, there are three nutrients that can supply the methyl group -

1) Folate/Serine
2) Choline/Betaine
3) Vitamin U

Remethylation is catalyzed by a specific enzyme for each nutrient -

1) Methionine synthase (MS) uses the cofactor B12 to transfer a methyl group from 5-methyltetrahydrofolate (folate) to homocysteine to form methionine and tetrahydrofolate.

2) Betaine homocysteine methyltransferase 1 (BHMT1) uses the cofactor zinc to transfer a methyl group from betaine to homocysteine to form methionine and dimethylglycine.

3) Betaine homocysteine methyltransferase 2 (BHMT2) uses the cofactor zinc to transfer a methyl group from Vitamin U to homocysteine to form two molecules of methionine.

We get most of our folate from vegetables and whole grains. Folate comes in various forms which our body converts into the active form MTHF. In fact, the major source of folate for many Westerners is folic acid added to processed wheat flour to make up for the loss of folate during milling. While a certain amount of folate we eat is already methylated, the main role of folate is that of a carrier. The same folate molecule accepts and donates a methyl group many times during its existence. The methyl group is supplied several enzymatic steps upstream by serine.

Betaine is abundant in whole grains. It functions as an osmoprotectant to the plant, so is found in most grains with the notable exception of rice, most of which is grown underwater. The major source of betaine in the typical American diet is bread, especially whole grain. In addition, a substantial amount of betaine is derived from choline. Choline is found in most whole foods, especially eggs, meat and whole vegetables. It is mainly used in phosphatidylcholine synthesis. Extra choline is broken down to make betaine. 

Betaine has three methyl units available that can feed into methylation pathways at various points. Betaine donates a methyl unit to homocysteine to produce methionine and dimethylglycine in a reaction catalyzed by betaine homocysteine methyltransferase. Dimethylglycine donates a methyl unit to tetrahydrofolate to produce sarcosine (methylglycine) and methylenetetrahydrofolate in a reaction catalyzed by dimethylglycine dehydrogenase. Sarcosine also donates a methyl unit to tetrahydrofolate to produce methylenetetrahydrofolate, this time in a reaction catalyzed by sarcosine dehydrogenase. The latter two reactions activate folate, which enables it to methylate homocysteine. 

Vitamin U (S-methylmethionine) from plants has two methyl units to donate as its reaction with homocysteine not only converts homocysteine into methionine, but itself is transformed into a second molecule of methionine. The reaction is catalyzed by the enzyme BHMT2 and mostly happens in the liver and kidneys. The major dietary source of Vitamin U are fresh vegetables and fruit.

Does Vitamin U contribute to methylation status in people? Assuming a maximum of 250 mg Vitamin U is taken each day from the diet (from a generous one liter of cabbage juice), that's 1.25 mmoles of Vitamin U or 2.5 mmoles of methyl groups. In a typical diet, methionine contributes 10 mmoles, choline contributes 30 mmoles, betaine contributes 26-75 mmoles, and folate (via methylneogenesis) contributes 5-10 mmoles of methyl groups per day. Assuming these estimates are correct, Vitamin U plays quite a modest role in the methylation status of people. However, it should be taken into consideration that not all of these nutrients give up their methyl groups. Methionine incorporated into proteins and choline used to make phosphotidylcholine are examples. 

For a vegan with a low protein diet and whose staple grain is rice, the contribution from Vitamin U is more significant as a percentage, though this diet may be low in total methylation capacity. It's not that Vitamin U is not a quality source of methyl groups - it's just that it's low in abundance in a natural diet compared to the other methyl donors. The fact that mammals have an enzyme devoted to its use demonstrates the importance Vitamin U has in the diet. To increase the contribution of Vitamin U towards methylation in people whose diet contain low concentrations of methyl groups, it is possible that larger amounts of Vitamin U via supplementation could be effective.


References

https://www.ncbi.nlm.nih.gov/pubmed/17209172

https://www.ncbi.nlm.nih.gov/pubmed/23196816

https://www.ncbi.nlm.nih.gov/pubmed/23661599

https://www.ncbi.nlm.nih.gov/pubmed/17413090

https://www.ncbi.nlm.nih.gov/pubmed/1128236

https://pubmed.ncbi.nlm.nih.gov/30871166/
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The methionine cycle and Vitamin U


Summary - The methionine cycle is a multistep enzymatic process than enables Vitamin U to be used as a source of methyl groups vital for gene regulation and the regeneration of creatine/ATP in muscles, as well as its use as a precursor of glutathione required to fight oxidative stress and inflammation.

This is a simple depiction of the four-step methionine cycle in our body. In the first step, the adenosyl group of ATP is transferred to methionine to form S-adenosylmethionine (SAM), thereby activating the methyl group of methionine. In the second step, SAM donates its methyl group to a range of acceptor molecules (notably DNA, guanidinoacetate, and phosphatidylethanolamines), also yielding S-adenosylhomocysteine (SAH). In the third step, the adenosyl group SAH is removed by hydrolysis leaving homocysteine. In the fourth step, homocysteine is either remethylated using one of three methyl donors to reform methionine (step 4a) or is directed into the transsulfuration pathway to form cystathionine (step 4b).

The methionine cycle has a myriad of functions including -

1. The generation of methylation capacity, 
2. The biosynthesis of cysteine as a component of proteins and glutathione, and as a precursor to taurine and hydrogen sulfide, 
3. The biosynthesis of polyamines from SAM. 

The most important function of the methionine cycle is to generate methylation capacity. A measure of our body's methylation capacity is the SAM:SAH ratio, i.e. the relative amounts of the two intermediates. If this ratio is low (below 4), the first enzyme in transsulfuration (cystathionine beta synthase) will have low activity and homocysteine will be remethylated to reenter the methionine cycle (step 4a). This tendency will continue until the ratio is above 4, at which point the relatively high concentration of SAM activates cystathionine beta synthase (CBS) resulting in excess homocysteine being funneled into the transsulfuration pathway. 

Another important function of the methionine cycle is the biosynthesis of cysteine via transsulfuration. Transsulfuration adds cysteine to that obtained from our diet as a component of protein (~50%). Cysteine is used as a building block in human proteins, is the catalytic center of the master antioxidant glutathione as well as acting as a precursor to molecules such as taurine and hydrogen sulfide. Increased oxidative stress will result in activation of CBS activity via allosteric binding by glutathione and transcriptional upregulation by hydrogen sulfide, nitric oxide and carbon monoxide. However, despite the negative health effects of high homocysteine levels (associated with cardiovascular disease) and low glutathione levels (associated with inflammation), the maintenance of methylation capacity trumps that of the provision of transsulfuration products.

The most common cause of a low SAM:SAH is a shortfall in the supply of dietary methyl donors. Other causes of low flux include shortages in vitamins that help catalyze reactions (e.g, folate, B12, B6), mutations in genes that encode enzymes involved in catalysis (e.g. MTHFR, CBS), and very low calorie diets.

There are several nutrients that can contribute methyl groups to the methionine cycle. Aside from methionine, which enters the methionine cycle directly, the other dietary methyl donors enter the methionine cycle via methylation of homocysteine. There are three enzymes known to catalyze this reaction in humans, with each enzyme acting upon a single methyl donor molecule. Other molecules that can contribute methyl groups must do so indirectly. Consequently, the three classes of dietary methyl donor are characterized by the enzyme that catalyzes the reaction with homocysteine and its substrate -

1. Betaine:homocysteine methyltransferase 1 (BHMT1) and betaine (trimethylglycine or TMG)
2. Methionine synthase (MS) and folate (5'-methyltetrahydrofolate or MTHF)
3. Betaine:homocysteine methyltransferase 2 (BHMT2) and Vitamin U (S-methylmethionine)

Betaine (trimethyl glycine) has three methyl groups, one of which is transferred to homocysteine to form methionine and dimethyl glycine. The other two methyl groups contribute to methylation, though via assimilation through the folate cycle. Dimethyl glycine dehydrogenase catalyzes the transfer of a methyl group from dimethyl glycine to tetrahydrofolate to produce 5, 10-methylenetetrahydrofolate. The other product, methyl glycine (sarcosine) yields the last methyl group to tetrahydrofolate in a similar reaction catalyzed by the homologue sarcosine dehydrogenase.

Betaine is plentiful in whole grains, with the notable exception of rice (betaine is an osmoprotectant in plants and it appears that under the wet conditions in which rice is usually grown betaine formation is suppressed). Betaine is also produced in our body from choline, which is abundant in the fatty component of food as phosphatidylcholine. Consequently, food with more naturally occurring fat such as meat, eggs, dairy and nuts are the richest sources of choline, with produce and grains contributing a lesser amount.

The active form of folate (Vitamin B9) is 5'-methyltetrahydrofolate, which supplies a methyl group to homocysteine to yield methionine and tetrahydrofolate. Once folate has donated its methyl group, it must be remethylated in the folate cycle to be reused. The primary source of these methyl groups is serine. Contrary to popular belief, folate itself is a minor dietary source of methyl groups. Even taking supplements labelled "methyl folate" or "activated folate" or eating green leafy vegetables provides minimal extra methylation substrate. With regards to its role in methylation, folate is better thought of as a carrier molecule analagous to homocysteine rather than as a methyl source.

Most methionine in our diet is found as a component of protein, which requires extensive digestion by a slew of enzymes to release methionine as an amino acid before it can enter the methionine cycle. Vitamin U (S-methylmethionine) is methionine with an extra methyl group, although unlike methionine, Vitamin U is rarely a component of proteins. It supplies a methyl group to homocysteine yielding two molecules of methionine. Vitamin U is abundant in vegetables and fruits, especially cruciferous (e.g. cabbage, kale) and stalky (e.g. celery, asparagus) vegetables.

The degree to which these methyl donors contribute to the methionine cycle is dependent upon our diet. In a diet rich in protein and fats, methionine and choline will be major sources. In a diet in which more calories are gleaned from whole grains, betaine will make a greater contribution. Folate and Vitamin U will make larger contributions in diets rich in fresh produce.



References


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Cabbage Juice Heals Peptic Ulcers





In the 1940s and 1950s, Dr Garnett Cheney from Stanford discovered that having his peptic ulcer patients drink one liter of fresh cabbage juice daily healed their stomach and duodenal ulcers 3-6 times faster than a bland diet alone (Cheney 1949; Cheney 1952; Cheney 1956). Chronic ulcers disappeared in 1-2 weeks depending on their severity. Dr Cheney was of the opinion that peptic ulcers resulted from a deficiency of a nutritional factor he termed Vitamin U, which was later identified as the amino acid S-methylmethionine, a plant product. While cabbages are a particularly rich source of Vitamin U, Cheney found that all raw plant products contain some Vitamin U. In addition to healing existing ulcers, Dr Cheney found that Vitamin U also prevented the formation of new ulcers.

How do ulcers form? Ulcers result from an imbalance in the digestive system between protective and destructive factors. An alkaline bilayer of mucus containing mucin protects the wall of the digestive tract from harsh elements such as stomach acid, infection by bacteria living in the digestive system, NSAIDs, and dietary factors like high salt and alcohol. In modern times, NSAIDs increasingly contribute to ulcer formation by inhibiting the mucus-stimulating function of our body's prostaglandins. When the mucus layer is depleted, these harsh elements irritate the epithelial cells lining the digestive tract causing inflammation and enabling deep infection. 

Ulcers are usually treated with combinations of proton pump inhibitors or H2 blockers that reduce acid production, antibiotics to treat bacterial infections (particularly Helicobacter pylori in the stomach), antacids to neutralize acid, and mucosal protectants such as prostaglandin mimics. Unfortunately, these only provide a temporary solution to the problem. Ulcers return soon after cessation of treatment. Excessive stomach acid is usually not the root problem, nor is H. pylori infection. Most people with ulcers produce a normal amount of stomach acid, and half the world's population has H. pylori yet remain ulcer-free. These facts indicate that while acid and infection contribute to the formation of ulcers, other factors are at play.

Given the findings of Dr Cheney, it's likely that eating a diet rich in Vitamin U promotes good gastrointestinal health. But how does Vitamin U work? In later studies, it was shown that Vitamin U has four properties that help maintain a healthy gut.

  1. Stimulating the release of mucin into the mucus layer, thereby protecting the walls from acid and bacterial infection (Watanabe 1996; Watanabe 2000; Salim 1991).
  2. Reducing inflammation by acting as a precursor to glutathione, the master antioxidant of the human body, via its conversion to cysteine (Szegedi 2008).
  3. Coordinating with other nutrients such as methionine, folate, B12, betaine, choline, SAMe and B6 to supply vital methyl groups required for optimal health (Suzue 1967).

Increasing the Vitamin U content of one's diet in combination with reducing the intake of elements that deplete the protective mucus layer has been shown to improve ulcerative conditions in the digestive system. A diet rich in fresh vegetables, vegetable juice and fruit, and low in salt, alcohol and sugars is a good approach for restoring the mucus bilayer in many people.


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