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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Vitamin U is a mucin secretagogue


Summary - Vitamin U is a nutrient abundant in vegetables and fruit whose main function is to stimulate the secretion of mucin and enable the formation of the mucous bilayer that protects the stomach from acid and Helicobacter pylori.

In the human body, Vitamin U heals and protects against peptic ulcers. It does so by stimulating the secretion of mucins onto the walls of the digestive tract, acting as a precursor to the biosynthesis of the master antioxidant glutathione, and supplies methyl groups for gene regulation, polyamine biosynthesis and a range of other molecules. Of these three functions, stimulating mucin secretion is the most direct way in which Vitamin U works.

In the stomach, there is an alkaline mucous bilayer gel that protects the stomach from gastric acid, pepsin digestion and bacterial infection. Mucus consists of two layers - a deep gel-like layer attached to cells and a superficial loosely-attached layer on top. The proteins that make up mucus are called mucins (MUC1, MUC5AC, MUC6), which are heavily-glycosylated proteins that attract water, thereby forming a gel. Mucins are made in foveolar cells lining the stomach and are stored in vesicles awaiting summons to the lumen. At the surface, some mucins stay attached to the cells and act as an anchor for the loosely-bound mucins to attach by disulfide bonds. When this mucous bilayer is disrupted, gastric juice can reach the lining of the stomach causing irritation and inflammation. Left long enough, a peptic ulcer may form.

Your body has a number of different ways to stimulate the secretion of mucin. The molecules that trigger secretion are called mucin secretagogues. The prime mucin secretagogue is prostaglandin E2, a hormone-like molecule that has many functions in the human body. It has a protective role in stomach function, suppressing production of gastric acid and pepsin, while at the same time promoting secretion of mucin and the alkaline molecule bicarbonate (Park et al). NSAIDs reduce prostaglandin E2 synthesis by inhibiting COX-1, leading to less mucin, less protection and a greater risk of ulcers.

Vitamin U (S-methylmethionine) is a nutrient found in all vegetables and fruit, and especially members of the cabbage family. Vitamin U protects the digestive tract by stimulating the secretion of mucin from the foveolar cells. In 1996, Watanabe et al. showed that exposing gastric mucous cells to L-cysteine or methylmethionine sulfonium chloride (MMSC or Vitamin U) prevented the formation of stomach ulcers caused by exposure to 50% ethanol. They demonstrated that Vitamin U and cysteine work in a similar manner via a sulfhydryl group. Interestingly, Vitamin U does not have a sulfhydryl group, but rather a sulfonium group. Consequently, Vitamin U is usually described as a latent sulfhydryl. The fact that Vitamin U and L-cysteine activities were inhibited by the pre-administration of the sulfhydryl inhibitor N-ethylmaleimide suggests that Vitamin U is active as a sulfhydryl. Vitamin U is stable at acid pH, so activation probably takes place in foveolar cells. 

In a follow up study, Watanabe et al. (2000) found that Vitamin U and cysteine induced the transport of vesicles containing mucin from deep within the cytosol to the cell surface for release into the stomach lumen, thereby forming a protective barrier. Interestingly, the movement they observed was independent of Ca2+ and cAMP. When signal transduction occurs via an endogenous molecule like prostaglandin-E2, there is a rise in the concentration of cAMP. When the P2 purinergic receptor is activated by ATP, there is an accompanying rise in Ca2+. Yet sulfhydryl-instigated movement did not induce a change in Ca2+ or cAMP levels. The authors suggested sulfhydryls promote mucus movement by a non-receptor mediated process.

Irrespective of how Vitamin U works, there's good evidence that drinking fresh vegetable juice or taking Vitamin U supplements may help restore your mucous bilayer, ease discomfort and heal your ulcers.

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