Longevity and Vitamin U

We age and die as a result of our body accumulating oxidative damage. For example, smoking creates oxygen radicals that damage lung cells. This damage reduces the function of these cells and when enough cells have been damaged or die, lung tissue fails to function and we die from lung failure. 

The best way to live your healthiest life is to reduce future oxidative damage as much as possible. The key to doing this is to restore and maintain high glutathione levels. Glutathione is the main antioxidant in your body that quenches the radicals that damage cells. 

Healthy glutathione levels have been associated with longevity. Studies have shown that centenarians have similar glutathione levels to that of young people. In contrast, people who die at a younger age almost always have a low level of glutathione, which almost certainly contributes to the degenerate condition. 

Can glutathione levels be restored? Evidence suggests they can. Studies on middle age people showed that taking supplements restored their glutathione levels to that of their younger counterparts in 24 weeks.  Studies on mice taking similar supplements found those who received supplements lived 24% longer than those who didn't. Furthermore, biochemical markers of good health improved with supplementation suggesting restoring these biochemical markers is probably a useful predictor of lifespan. 

Does this mean humans taking supplements that restore glutathione levels will live longer lives? As humans aren't mice, we can't extrapolate this data to human longevity, but the results so far are promising.

What's the best way to restore glutathione levels? Glutathione is made up of cysteine, glycine and glutamic acid. In these studies, NAC and glycine are the two amino acids that improved health and longevity in mice and improved health biochemical markers in people (roughly 7 g per day in people). Note that NAC and glycine levels were low in these middle aged people whereas glutamic acid levels were normal, and that NAC is converted into cysteine before becoming a component of glutathione.

Can Vitamin U be substituted for NAC? Quite possibly, although this has not been tested directly. Vitamin U is an amino acid (S-methylmethionine) that is produced naturally by all flowering plants and is found in all produce, especially stalky and cruciferous vegetables. Vitamin U is integrated into the human body by specific enzymes in the liver and kidney. One advantage of taking Vitamin U over NAC is that these enzymes in the liver and kidney specifically regulate the integration of Vitamin U, converting it into cysteine-->glutathione when needed without any of the potential side effects of NAC dosing.

Note that while restoring glutathione levels will minimize further damage from oxidative stress, it won't directly reverse existing damage. However, restoring healthy glutathione levels will allow your body's natural repair systems to heal your body the best they can. 

https://pubmed.ncbi.nlm.nih.gov/21795440/

https://pubmed.ncbi.nlm.nih.gov/35268089/

https://pubmed.ncbi.nlm.nih.gov/12486409/

Coffee, GERD, stomach ulcers and Vitamin U

Drinking our morning coffee is one of life's little pleasures. Unfortunately, coffee is notorious for inciting acid reflux, GERD, and worsening peptic ulcers. This is especially the case with more heavily roasted coffees and instant coffee. 

What is it about coffee that makes it so problematic? The underlying reasons for the irritability of coffee are a little mysterious. People often cite the acidity of coffee, and it does seem that coffee that tastes less acidic is less harsh on the stomach. However, considering the stomach has a pH that makes coffee appear comparatively mild, there is likely more to this than meets the eye. Furthermore, there are many foods that taste acidic that don't elicit the same response. Malic acid in green apples is very tart and lemons are barely edible for the amount of citric acid they contain, yet eating these fruits doesn't typically cause acid reflux (they may make ulcers sting, but that's another story).

The classic stimulant caffeine almost certainly contributes to acid reflux to some extent. Caffeine definitely relaxes the esophageal sphincter, which is a muscle whose function is to separate stomach acid from the esophagus. The stomach is full of concentrated HCl, which would damage the lining of the stomach except for the presence of a thick alkaline mucus bilayer maintained by prostaglandins and certain nutrients such as Vitamin U. However, decaffeinated coffee can still cause acid reflux so there's more to it than just caffeine.

Stomach acid has several functions, from inhibiting the growth of bacteria to unraveling dietary protein and providing the right pH for the proteolytic actions of pepsin. What isn't widely known is that the stomach isn't full of acid at all times. In fact, eating stimulates the production of the hormone gastrin, which via a chain of events results in the secretion of HCl into the stomach. The key dietary component that stimulates gastrin release is protein. Scientists were curious to understand what is it about protein that triggers this response. Protein consist of 20 types of amino acids that have different properties. The aromatic amino acids phenylalanine and tryptophan were by far the most stimulatory (the other aromatic amino acid tyrosine was not tested due to solubility issues).

The fact that aromatic amino acids were most stimulatory may be quite revealing. Other amino acids all have an acidic group (in fact, some even have two), so it's not acid per se that is the issue. It would seem that the aromatic side chain is the effector (chemically, aromatic simply means that it has a benzene ring). This is where coffee comes in. Coffee has over 2000 compounds, some of which have benzene rings just like the aromatic amino acids. These are collectively referred to as cinnamic acids, and are present in many vegetables, fruits and other plant-based products. Examples include caffeic acid, p-coumaric acid, ferulic acid, and esters thereof. Though it hasn't been demonstrated conclusively, one may wonder whether some of the adverse gastronomical effects of coffee may in part be due to the fact that coffee is an extract containing a wide array of compounds that bear an uncanny resemblance to known acid producers. As extracts, cinnamic acids in coffee are easily accessible. Furthermore, it has been estimated that coffee is the richest sources of cinnamic acids in the Western diet at up to 1 g per day.

Can Vitamin U help with acid reflux? As the mode of protective action afforded by Vitamin U is via the stimulation of mucus secretion in the stomach, Vitamin U should protect the lining of the stomach to some extent. There is evidence that Vitamin U can help maintain mucosal integrity in other parts of the alimentary canal such as the esophagus. However, the mucus lining the esophagus is thin and not built to withstand concentrated hydrochloric acid. The protective effects conferred by mucoprotectants such as Vitamin U are most effective when used in conjunction with dietary modification that avoids the worse offenders like coffee. Drinking lightly roasted low-acid coffees still have plenty of caffeine and are less likely to cause problems.

Further reading

1. https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0010(19990301)79:3%3C362::AID-JSFA256%3E3.0.CO;2-D
2. https://www.sciencedirect.com/science/article/pii/S2090123219300025
3. https://pubmed.ncbi.nlm.nih.gov/6806140/

Allergies and Vitamin U

At this time of the year, allergies are a seasonal problem for many people. With the coming of pollen also comes itchy eyes, a runny nose, an annoying cough and maybe more serious conditions such as asthma or hives. Cells in our immune system called mast cells produce histamine, which triggers an inflammatory response by binding H1 receptors. Our blood vessels dilate and fill with fluid to help get rid of allergens and to counteract the narrowing causes by the build up of mucus. Unfortunately, our bodies tend to overreact and produce way too much histamine. Antihistamines like loratadine (Claritin), cetirizine (Zyrtec), diphenhydramine (Benadryl) work by blocking the binding of histamine to these receptors.

Our body has a few mechanisms that can remove excess histamine from our body. One of the most important is the enzymatic action of histamine N-methyltransferase. HNMT catalyzes the methylation of histamine using the universal methyl donor S-adenosylmethyltransferase (SAM) as its source of methyl groups. Methylated histamine can no longer bind to the H1 receptor and cannot trigger more inflammation. Methylhistamine is removed from our body in our urine. People with polymorphisms in the gene encoding HNMT often present with a runny nose, hives and peptic ulcer disease.

Vitamin U is a natural support for decreases in methylation capacity caused by allergies. Vitamin U carries two methyl groups that contribute to the formation of SAM. Taking Vitamin U in the form of fresh cruciferous or stalky vegetables, or as a supplement, helps replenish methylation capacity when you are struck by allergies. Allergens can have a draining effect on the whole body, with low methylation capacity reducing our ability to maintain good health and can lead to low methylation conditions such as peptic ulcers and histamine intolerance.

Vitamin U is not a drug: it will not stop a runny nose dead in its tracks like antihistamines can. Nor will Vitamin U be effective in treating anaphylactic shock. If you have a severe allergic reaction, please immediately rush to the hospital for treatment. Vitamin U simply aids our body's natural mechanism for removing excess histamine. Ensuring your dietary intake of Vitamin U is adequate will complement drugs in your battle with seasonal and persistent allergies.

Further reading

• https://pubmed.ncbi.nlm.nih.gov/30744146/
• https://pubmed.ncbi.nlm.nih.gov/17490952/

Neural tube defects and Vitamin U

By Centers for Disease Control and Prevention - Centers for Disease Control and Prevention, Public Domain, https://commons.wikimedia.org/w/index.php?curid=30509337

 

Summary - Vitamin U may play a supportive role in correct neural tube formation, a process that depends on the methylation of dUMP to form dTMP via the folate cycle. The folate and methionine cycles work together to meet the methylation needs of the body. Low cellular methylation status diverts methyl groups from the folate cycle to the methionine cycle, thereby decreasing dTMP synthesis and increasing the risk of neural tube defects. Dietary methyl donors that enter the methionine cycle directly (e.g. methionine, betaine, Vitamin U) support neural tube formation by reducing this methyl group drain. While folate is the most important factor affecting neural tube formation, folate intake may not be sufficient in and of itself due to other factors such as polymorphisms within these two pathways and intake of other components that contribute to methylation homeostasis. Talk to your dietitian before conception about designing a diet that reduces the risk of neural tube defects in your baby.

Neural tube defects (NTDs) are a collection of medical conditions in which the neural tube of the baby does not form completely during early development, exposing the spinal cord and/or brain with permanent disability resulting. Two common neural tube defects are spina bifida (spine) and anencephaly (brain). 

What causes NTDs? Like many conditions, NTDs result from a combination of environmental and genetic factors. The most common environment factor is the insufficient intake of folate by the mother just before and during the first few weeks of pregnancy. Folate is a vitamin (B9), and is therefore an essential component of one's diet. In the 1950s it was noted that pregnant women taking anti-folate drugs to treat cancer gave birth to babies afflicted with congenital abnormalities like NTDs (Safi 2012). It was established that folate is essential for embryonic development, that women whose folate levels were low were at greater risk of having babies with NTDs, and that supplementation by the mother-to-be with folate substantially reduced the risk of NTD occurrence (Smithells 1980; Wald 1991). Folate supplementation is the most effective way to prevent NTDs, reducing risk by 50-70%. Consequently, medical authorities recommend young women ensure their diet contains 400 ug of folate per day through food and supplements in case they become pregnant.

How does folate prevent neural tube defects? The function of folate is to transfer methyl groups generated from serine to a range of molecules throughout the cell. In embryos, these methyl groups are essential to make nucleotides required for DNA synthesis. There are many compounds that are methylated as a result of the action of folate. However, there is one for which there is evidence that a shortage of results in neural tube defects - dTMP (deoxythymidylate). There are four nucleotides used to make DNA - abbreviated to A, T, C, G. dTMP is a precursor in the formation of dTTP, usually shortened to T. In humans, the nucleotide dTMP is made from dUMP by the transfer of a methyl group from folate. Embryos supplemented with dTTP do not develop neural tube defects despite very low folate levels, indicating that dTMP shortage is the causal factor (Leung 2013). At conception, nucleotides must be synthesized in utero, and therefore a shortage of folate results in low production of dTMP, which in turn results in NTDs.

Figure 1 - A simplified depiction of the folate cycle. The enzymes responsible for catalyzing each step are -

1. Serine hydroxymethyltransferase

2. Thymidylate synthase

3. Dihydrofolate reductase

4a. 5,10-methylenetetrahydrofolate dehydrogenase NADP+

4b. 5,10-methenyltetrahydrofolate cyclohydrolase

4c. Formate-tetrahydrofolate ligase

5. Phosphoribosylaminoimidazolecarboxamide formyltransferase

6. Methylenetetrahydrofolate reductase

7. Methionine synthase

N.B. 4a-c are three components of MTHFD1

Which folate should you take and where should you get it from? 

First a note on nomenclature. The term 'folate' is commonly used to refer to any of the components of this pathway plus other forms like folic acid and folinic acid. Naturally-occurring folate is a mixture of these forms, with the exception of folic acid, which is a non-natural, oxidized version that is relatively stable and therefore used to fortify food in which natural folate has been removed or degraded. Vitamin supplements usually contain either folic acid or 'methyl folate' or 'activated folate', which usually refers to 5-methyltetrahydrofolate.

The best source of natural folates are green leafy vegetables, although all vegetable sources (including fruit and grains) are reasonable sources. Folic acid is a form of folate that is often added to processed grains that have been polished, e.g. wheat flour, white rice. For most people, it makes little difference whether their folate is derived from natural or synthetic sources. The important factor is getting the right amount. However, some people do not metabolize synthetic folic acid effectively and as such can actually suffer from a deficiency in functional folate even when their serum levels of folic acid seem sufficient (Bailey and Ayling 2009). Sometimes too much folic acid can even cause fertility problems (Cornet 2019). 

There are other components in the folate cycle that also have an effect on neural tube formation, albeit to a lesser extent. For example, vitamin B12 is an essential cofactor for the enzymatic conversion of 5-MTHF to THF, and low B12 levels have been linked to NTDs (Li 2009). Another example is Vitamin B6, which is a coenzyme for serine hydroxymethylfolate transferase. Cobalt is a component of B12 and therefore is vital for methionine synthase function.

Where does genetics fit in? While folate supplementation reduces risk, unfortunately genetic polymorphisms in the mother are responsible for the majority of NTDs cases (Copp 2013). Mutations of genes in the folate cycle and other branches of one carbon metabolism (methylation) are particularly relevant. There are many enzymatic steps in the folate cycle, and each enzyme is encoded by a gene. Polymorphisms are nucleotide changes (mutations) in these genes that differ from that found in the majority of people. Most polymorphisms have no significant physiological effect by themselves, but may have an effect in combination. However, there are a few polymorphisms that do correlate with the occurrence of NTDs, such as MTHFR C677T and MTHFD1 R653Q (Copp 2013). 

Genetic testing is becoming an increasing-popular tool to identify polymorphisms. Though it is tempting to do so, it is important to not assume that polymorphisms necessarily result in reduced physiological function. Human physiology is not fully understood and often contains redundancies that can mask over minor metabolic blocks. The correct way to establish whether there are deficiencies within the folate cycle is through biochemical analysis of the various folate metabolites. Biochemical analysis in combination with genetic analysis is used by specialists to establish whether there is a functional deficit in the mother that results in heightened risk of NTDs in her baby. Consult with your doctor or dietitian to determine if you have polymorphisms, and if you do, whether these actually affect your metabolism (often they don't) and what measures can be taken to relieve any metabolic blocks.

Aside from the folate cycle, there is another cycle that is even more important in meeting our methylation needs. The methionine cycle is the way in which the methyl donor S-adenosylmethionine (SAM) is generated (methionine cycle). SAM is the methyl donor for just about all methylation reactions, with the notable exception of those in the folate cycle. It has been shown that a functioning methionine cycle is essential for correct neural tube formation (Leung 2017). When there is a shortage of methyl groups in the methionine cycle (low S-adenosylmethione:S-adenosylhomocysteine), methyl groups are directed from the folate cycle into the methionine cycle. Instead of being used to make nucleotides, 5,10-methylenetetrahydrofolate is reduced by MTHFR to make 5-methyltetrahydrofolate, which donates its methyl group to the methionine cycle in a reaction catalyzed by methionine synthase. The folate molecule is conserved within the folate cycle, but must be remethylated. When maternal folate levels are low and flux through the folate cycle is already slow, this shunt may reduce methylation capacity in the folate cycle to critical levels. 

The methionine cycle obtains a large amount of its methyl groups from the folate cycle. This shunt operates at moderate levels most of the time - this is actually a normal process. In addition, the methionine cycle obtains methyl groups from methionine, betaine and Vitamin U. Similar to the methionine synthase reaction, betaine and Vitamin U donate methyl groups to homocysteine via enzyme-catalyzed reactions. Importantly, methyl groups in the methionine cycle cannot enter the folate cycle. For example, SAM from the methionine cycle cannot substitute for 5,10-MeTHF required for dTMP synthesis. Low maternal methionine levels pre- and post-conception are associated with a heightened risk of neural tube defects (Shaw 2004). There is evidence that betaine entering the methionine cycle reduces the flow of methyl groups from the folate cycle, which in principle should support 5,10-MeTHF levels (Benevenga 2007).

Where does Vitamin U fit into all this? It should be emphasized that there has not been any scientific research testing whether Vitamin U supplementation can prevent NTDs. The studies have simply not been done. However, there is some genetic evidence that suggests that Vitamin U may play a role in correct neural tube formation. 

• Vitamin U supplies methyl groups to mammals via its reaction with homocysteine to form methionine catalyzed by the enzyme BHMT2. This is very similar to that of betaine, though whether Vitamin U plays this role in embryonic tissue has not been investigated. 

• Vitamin U is abundant in vegetables, the benefits of which have been long known in preventing neural tube defects. While the presence of folate is most likely the primary factor, it is possible that some of the benefits conferred by eating vegetables are due to the provision of methyl groups from Vitamin U.

• A preconception diet rich in methionine reduces the prevalence of neural tube defects. Vitamin U is essentially methionine with an extra methyl group. One molecule of Vitamin U actually supplies two molecules of methionine, one being the newly-methylated homocysteine, the other being the demethylated Vitamin U.

• Studies have shown that methylation in the embryo is supplied by methyl groups from both the folate cycle and betaine. If we assume that methionine synthase and BHMT1 contribute to embryonic methylation, then Vitamin U is also likely to make a contribution. It is logical that the benefits of green vegetables in preventing neurological abnormalities is due to the combined effects of folate, betaine and Vitamin U, with the emphasis on folate.

Summary

• Folate is absolutely necessary at some level to provide the embryo nucleotides during the first weeks following conception. It cannot be replaced by other molecules.
• Folate requirements may be lowered as long as adequate levels of methyl groups are provided by methionine and betaine from the methionine cycle. 
• Though its role in fetal development has not been investigated, it is likely that Vitamin U has a similar role to that of methionine and betaine, and would be of greater importance for people whose diet is low in protein and fat such as vegans.

Further Reading

• Shaw et al 2004 https://pubmed.ncbi.nlm.nih.gov/15234930/
• Zhang et al 2015 https://pubmed.ncbi.nlm.nih.gov/25466894/
• Froese et al 2019 https://pubmed.ncbi.nlm.nih.gov/30693532/
• Halsted et al 2002 https://pubmed.ncbi.nlm.nih.gov/12122204/
• Shin et al 2010 https://pubmed.ncbi.nlm.nih.gov/20220206/
• Bailey and Ayling 2009 https://pubmed.ncbi.nlm.nih.gov/19706381/
• Cornet et al 2019 https://pubmed.ncbi.nlm.nih.gov/31205715/
• Huennekens 1969 https://pubmed.ncbi.nlm.nih.gov/4891866/
• Purohit et al 2007 https://pubmed.ncbi.nlm.nih.gov/17616758/
• Duncan et al 2013 (1) https://pubmed.ncbi.nlm.nih.gov/23857220/ 
• Duncan et al 2013 (2) https://pubmed.ncbi.nlm.nih.gov/23143835/
• Teng et al 2012 https://pubmed.ncbi.nlm.nih.gov/23014492/
• Rinehart and Greenberg 1948 https://pubmed.ncbi.nlm.nih.gov/18859393/
• Leung 2013 https://pubmed.ncbi.nlm.nih.gov/23935126/
• Leung 2017 https://pubmed.ncbi.nlm.nih.gov/29141214/
• Blom 2006 https://pubmed.ncbi.nlm.nih.gov/16924261/
• Benevenga 2007 https://pubmed.ncbi.nlm.nih.gov/17413090/
• Bertolo and McBreairity 2013 https://pubmed.ncbi.nlm.nih.gov/23196816

Vitamin U is metabolized by the enzyme BHMT2

Summary - BHMT2 is the enzyme that catalyzes the assimilation of Vitamin U into our body. Made at high levels in the liver and kidneys, BHMT2 catalyzes the transfer of a methyl group from Vitamin U to homocysteine. This reaction plays an important role in the maintenance of healthy glutathione levels by contributing to an optimal methylation state, which drives existing and newly-formed homocysteine into the transsulfuration pathway and towards glutathione synthesis.

Vitamin U is a nutrient that is ubiquitous and abundant in vegetables and fruit. It is a noted dietary mucin secretagogue that has been shown to play an important role in healing and preventing peptic ulcers. It appears that Vitamin U interacts directly with the cells lining the stomach and induces secretion through a non-receptor mediated mechanism, different to that used by other secretagogues (more). 

Vitamin U doesn't just interact with the stomach. In fact, much of Vitamin U is absorbed by the small intestine and taken to the liver where it is metabolized. It is assimilated into our body via the methionine cycle (more). The enzyme that is responsible for Vitamin U assimilation is BHMT2 (Betaine Homocysteine Methyl Transferase 2). BHMT2 catalyzes the transfer of a methyl group from Vitamin U to homocysteine to produce two molecules of methionine. These products enter the methionine cycle where they donate methyl groups to form the universal methyl donor SAM and eventually are converted back into homocysteine. The fate of homocysteine is determined by the methylation status in the cell. A low SAM:SAH ratio results in homocysteine awaiting the appearance of new methyl donors in the form of Vitamin U, betaine and methyl folate for reentry into the methionine cycle. A high SAM:SAH ratio results in homocysteine entering the transsulfuration pathway, eventually forming cysteine and glutathione.

BHMT2 is well-expressed in the liver and kidneys (top 5% of proteins in these organs by abundance) (more) and is expressed at low levels in many other tissues throughout our body (more). 

High expression kidney, liver

Moderate expression thyroid, adrenal, pancreas, gallbladder, ovaries, rectum

Low expression nasopharynx, bronchus, stomach, duodenum, small intestine, colon, testis, epididymis, prostate, endometrium, fallopian tubes, heart muscle, skeletal muscle

Examples

BHMT2 is expressed at low, but measurable levels in the gastric glands. Not expressed in the gastric pits or muscle layer (more). 

BHMT2 is expressed at moderate levels in the thyroid gland (more).

BHMT2 is expressed at moderate levels in the mucosa lining the gallbladder (more).

BHMT2 is expressed at high levels in the renal tubules, but not in the renal glomeruli (more).

BHMT2 is expressed at high levels in hepatocytes, but not in bile duct cells (more).

To what extent these antibody stains indicate function of BHMT2 remains an open question. If the low expression of BHMT2 in the stomach is actually responsible for the protection afforded by Vitamin U, then the similar levels of expression in other tissues may indicate that Vitamin U has a physiological function in those tissues too. However, this remains to be scientifically investigated and does not constitute medical advice.

How was BHMT2 discovered?

Around 1940, scientists at the Lankenau Hospital Research Institute in Philadelphia were investigating the effects of oxidation on the uptake and metabolism of proteins. Gerrit Toennies was a chemist focusing on making forms of methionine and cysteine that had undergone oxidation to varying degrees. Mary Bennett fed these oxidized amino acids to rats to further our understanding of how animals use sulfur amino acids. They found that when the milk protein casein was chemically oxidized, it was no longer a viable source of protein for rats. Most proteins are made up of 20 types of amino acids. The scientists discovered that methionine and tryptophan were the two types of amino acid that were irreversibly oxidized (more).

During these studies, Toennies made a methionine derivative that was a little different. By reacting methionine with methyl iodide, methionine was methylated at the sulfur again, converting the sulfur into a sulfonium. Bennett fed this methionine sulfonium to rats in place of methionine. For 5 days, the rats did not grow. On the 6th day, the rats suddenly started growing at the same rate as the control rats being fed methionine (more).

What happened to the rats? Bennett suggested that the rats "may have developed a special mechanism for taking care of the extra methyl group" that allowed the sulfonium to be converted into methionine. This special mechanism was probably an enzyme that at that time had yet to be discovered. In 1959, Shapiro and Yphantis revealed that the liver expresses an enzyme that converts Vitamin U into methionine by methyl transfer to homocysteine (more). The gene encoding this activity was characterized in 2000 by Chadwick and named BHMT2 due to its resemblance to another liver enzyme BHMT1 (more). It was shown by the Garrow lab in 2008 that purified BHMT2 enzyme catalyzed the reaction between Vitamin U and homocysteine (more). 

It was hypothesized by Toennies that sulfoniums could have a biological role and it was speculated that methylmethionine sulfonium could exist naturally. In 1954, this hypothesis was confirmed by McRorie and others, extracting this compound from cabbage. Interestingly, the latter linked the chemical properties of their newly-discovered compound with those of a recently-discovered Vitamin U, and proposed that this compound was a source of methionine as well as a methyl donor (more). 

Does expression of BHMT2 depend on the presence of Vitamin U? From the studies of Bennett, it would seem that a lack of methionine might induce BHMT2 expression in rats rather than the presence of Vitamin U. For comparison, expression of the related enzyme BHMT1 in rat liver is induced 4-fold when methionine levels are low/choline normal and an additional 2-fold in the presence of betaine (more). However, not much research has gone into addressing BHMT2 expression, especially in humans. 

Mouth ulcers and Vitamin U

Summary - Mouth ulcers result from a breach of the mucous layer that protects the lining of the mouth and an underlying inability to repair the mucous layer quickly. Taking Vitamin U in the form of fresh vegetable juice and/or supplements is a great way to naturally heal mouth ulcers. Talk to your doctor or dentist.

Mouth ulcers (aphthous ulcers or stomatitis) are small, painful, circular sores that form in the lining of the mouth. They are very common. Right this minute, 1-2% of people have a mouth ulcer. Over a lifetime, about half of the US population will get at least one if not many. They mainly afflict teenagers. Ulcers normally heal spontaneously in one to two weeks, although they can reoccur many times. Recurrent ulcers indicate an underlying health problem. Sores in the corner of the mouth or outside the mouth are not ulcers and should be treated differently.  

Why do I have a mouth ulcer? 

The lining of your mouth is covered by a thin layer of mucus. The main purposes of this mucus is to protect the lining of the oral cavity from physical and chemical damage, infection, and to help digest food. Mouth ulcers develop when the protective mucus layer is breached and the body shows a delayed repair response with non-specific oral bacteria infecting. The integrity of the mucus layer is a function of constructive vs destructive factors. 

Destructive factors

Biting your mouth while eating or from a nervous habit is probably the most common way ulcers start. Physical or chemical damage from food is another very common cause - 

• Crusty food like bread or toast
• Crispy food like chips
• Salty food like pretzels
• Sweet food like candy
• Sticky food like cookies
• Sour food like vinegar
• Hot food like coffee

Abrasive, salty and hot foods/drinks physically damage the mouth. Sour foods/drinks chemically burn the mouth instantly. Sweet and sticky foods burn slowly by feeding oral bacteria, which metabolize sugars to produce corrosive acids. 

Drugs are another destructive factor. Alcohol is oxidized by oral bacteria to acetaldehyde, which is toxic and a carcinogen (Tagaino et al, 2019). Some acetaldehyde is even produced from sugar by oral bacteria. Acetaldehyde is also found in cigarette smoke (Sprince et al, 1975). As with peptic ulcers, NSAIDs like aspirin inhibit prostaglandin E2 synthesis which reduces mucin secretion. People swishing aspirin in their mouth to quell inflammation are actually slowing down ulcer healing (Slomiany and Slomiany, 2000).

Poor dental hygiene is yet another destructive factor. Harsh brushing makes tiny holes through which corrosive agents can meet the cell surface. Ineffectual or nonexistent brushing leaves food and bacteria in position to generate more organic acids and acetaldehyde.

Constructive factors

The major factor protecting the mouth is mucus. There are five kinds of mucin produced in the mouth - MUC5B and MUC7 being the most important (Frenkel and Ribbeck, 2015). MUC5B is a very long protein rich in serine and threonine amino acids to which glycans attach. These glycans attract water to form a gel and gives your mouth that slippery feeling. The protein overall looks likes a bottle brush with one end attached to the cell. MUC7 is similar, but is unattached and therefore flows freely aiding in formation of the soft bolus from food. MUC5B proteins form polymers via disulfide bonds. Cysteine is unusually common in MUC5B and is essential for disulfide bond formation.

A shortage of many dietary factors have been suggested to cause mouth ulcers. Examples include vitamin B9 (folate), vitamin B12, vitamin C, vitamin E, selenium. All play a role in antioxidation, and it makes sense that these nutrients are low in ulcers as the environment shows signs of oxidative stress (elevated malondialdehyde and depressed glutathione)(Arikan et al, 2009). 

Despite this speculation, however, the evidence has been inconclusive. There are certainly some patients who respond well to supplementation with one or another of these micronutrients. However, many times mouth ulcers occur in people with no apparent deficiency and/or supplementation has no effect. Considering that some of these micronutrients work in some cases, it's possible that they help in an indirect way, or that chronic mouth ulcers are indicative of a systemic redox imbalance. For example, chronic ulcers are more prevalent in those with other problems in their digestive tract (Brailo et al, 2007).

Can Vitamin U help heal and prevent mouth ulcers?

The use of Vitamin U to treat or prevent mouth ulcers has undergone little investigation (Kato and Takayasu, 1961). Vitamin U has been shown to be a useful treatment for gum disease (Sulym, 2016), and sulfur compounds like cysteine are effective in quenching the damaging effects of acetaldehyde in the mouth, particularly when combined with vitamins B1 and C (Sprince et al, 1975; Syrjanen et al, 2016).

The fact that Vitamin U has been shown to heal and prevent peptic ulcers by stimulating the release of mucin suggests that it may also have this function in other parts of the digestive tract which also secrete mucin (Watanabe et al, 2000). One can't help but wonder whether mouth ulcers have a similar etiology to its more dangerous relatives. If this is indeed the case, one may speculate as to whether Vitamin U or a metabolic derivative could have this effect on the release of mucin from not only the mouth or other parts of the alimentary canal, but even other epithelial tissues, including the lungs, trachea, nose and eyes.  

Vitamin U may also support mucosal function in indirect ways. Firstly, Vitamin U yields cysteine, which is the rate-limiting component of glutathione, the master antioxidant that fights oxidative stress. Secondly, the relatively large amount of cysteine required to tether mucin to the epithelial tissue means that extra cysteine in the form of Vitamin U may prove useful. Thirdly, much of the glycans that attach to mucins are themselves sulfated, requiring more sulfur. 

Many people, especially those whose diet is low in the sulfur amino acids methionine and cysteine, have limited antioxidant capacity due to having low levels of glutathione. For those people, alternative sources of sulfur amino acids like Vitamin U are an important alternative source. Drinking freshly-made vegetable juice or taking Vitamin U supplements in combination with the cessation of destructive practices will probably help clear up your current mouth ulcer and help prevent future ulcers.

Vitamin U complements H2 blockers

Summary - H2 blockers are drugs used to reduce stomach acid in people who have pain due to stomach ulcers. Vitamin U in the form of fresh vegetable juice or supplements can be used alongside H2 blockers to speed up the restoration of the protective mucous bilayer.

The human stomach is a very acidic environment. The pH of a correctly-functioning stomach is 1.5 - 3. The acidity of gastric juice is due to hydrochloric acid (HCl), which is produced by parietal cells in the upper parts of the stomach (fundus and cardia). Parietal cells produce acid using enzymes called proton pumps (H+/K+ ATPase), which use the energy derived from the hydrolysis of ATP to pump H+ into the stomach. It is the protons (H+) that cause acidity. 

The parietal cells pump acid into the stomach in response to signal molecules binding receptors. There are numerous kinds of receptors that respond to different stimuli, either positively or negatively. The most important for acid production are the H2 histamine receptors. Protein in food is broken down in the stomach by acid and the enzyme pepsin to form peptides. These peptides stimulate the release of the hormone gastrin from G cells in the stomach and duodenum. Gastrin stimulates the release of histamine from ECL cells. Histamine binds receptors in the base of parietal cells where it stimulates the movement of proton pumps to the apical surface, where they pump acid into the stomach cavity (lumen). This acid accelerates this whole cycle, breaking down more proteins in food by hydrolysis as well as activating pepsin.

H2 blockers bind to the H2 receptors, which stops histamine from binding. If histamine can't bind, the levels of acid in the stomach remain fairly low and the corresponding pH relatively high. (H2 blockers are often referred to as H2 antagonists because they block the binding of histamine without itself stimulating the function of the receptor, an important distinction from agonists). 

H2 blockers were invented in the 1960s and have to a large extent been superseded by proton pump inhibitors due to the latter's more potent acid-suppressing abilities. Commonly used H2 blockers include omeprazole (e.g. Prilosec), famotidine (e.g. Pepcid) and cimetidine (e.g. Tagamet). Ranitidine (e.g. Zantac) was the most prescribed drug in the US during the 1980s, but the FDA has recently banned its sale due to carcinogenic impurities. 

Stomach ulcers and gastroesophageal reflux (GERD) are conditions characterized by pain caused by stomach acid coming into direct contact with the lining of the stomach and esophagus, respectively. Contrary to popular opinion, these conditions are rarely caused by excessive production of stomach acid. In fact, the acidity in the stomach of those with stomach ulcers is typically low (i.e. relatively high pH). GERD is caused by normal stomach acid coming into contact with the esophagus, an organ that is not designed to withstand such exposure. Unlike the stomach, the esophagus is not coated with a protective alkaline mucous bilayer and is very sensitive to contact from even small amounts of gastric juice.

One unfortunate problem with taking H2 blockers for stomach ulcers is that they reduce the secretion of mucin (Ichikawa et al., Diebel et al). So while they reduce pain by reducing the amount of acid produced, they also increase the risk of pain by weakening the mucous bilayer. 

Vitamin U is a nutrient abundant in vegetables and fruit that stimulates the secretion of mucin in the stomach. As fresh vegetables and fruit have been a major component of our diet for a very long time, it is reasonable to conclude that dietary Vitamin U plays an important role in the maintenance of optimal stomach function. 

Can Vitamin U be combined with H2 blockers? 

Considering Vitamin U stimulates mucin secretion and H2 blocker reduce it, one may wonder whether Vitamin U can be taken with H2 blockers to negate the negative effects. The evidence suggests yes. In 2009, Ichikawa et al. showed that co-administration of Vitamin U with famotidine reversed the mucin-blocking effects of famotidine without affecting the acid-suppression effects. These results suggest that Vitamin U can add another level of protection to the gut in those taking H2 blockers.

Considering these findings, drinking fresh vegetable juice daily or taking Vitamin U supplements may help restore your mucous bilayer, ease discomfort and heal your ulcers.

High salt consumption may cause stomach ulcers

Summary - High salt consumption is a risk factor for the development of gastritis, gastric ulcers and gastric adenocarcinoma. If you have a stomach ulcer and your salt consumption is high, reducing the amount of salt you eat might help heal your ulcer, especially in combination with other treatments like antibiotics and Vitamin U. Talk to you doctor about your options.

(For clarification, "peptic ulcer" usually refers to ulcers in either the stomach or the duodenum. A "gastric ulcer" is another name for a stomach ulcer.)

The two most cited risk factors for the development of stomach ulcers are infection with Helicobacter pylori and taking NSAIDs (Mayo Clinic, 2020a). High dietary salt is another risk factor that is lesser known, though it has long been considered a risk factor in the development of stomach cancer (Mayo Clinic, 2020b; Cromer et al, 1949). Stomach ulcers and stomach cancer are two different conditions, and ulcers do not automatically lead to stomach cancer. However, these two conditions result from a similar set of risk factors, include high salt intake. What determines whether you develops ulcers or cancer may lie in genetics, diet, and to a certain extent, luck.

 

It has been long noted that at times when salt consumption within a population is low, stomach ulcers are rare (Sonnenberg 1986 and references within). For example, prior to the French Revolution, salt was heavily taxed in France as a means of raising crown revenue. Salt consumption was light among the general population. and the incidence of stomach ulcers was low. As salt taxes were repealed, salt consumption especially via its use as a food preservative increased. Salt consumption in the Western world peaked in the early 20th century, declining with the invention of alternative forms of preservation like canning and refrigeration. Throughout this period, mortality due to stomach ulcers rose, peaked, then declined in lockstep with salt use. 

Another way to show a relationship between salt intake and stomach ulcer prevalence is to look at these factors in different countries at a given time. Countries in which salt intake is high (e.g. Japan, Portugal, Spain) tend to have higher mortalities from stomach ulcers than those in which salt intake is low (Sonnenberg 1986). 

Does this mean your stomach ulcer is caused by eating too much salt? On the one hand, your ulcer is caused by something, and if your diet is heavy in salt, it might be a contributing factor. On the other hand, while the evidence is quite suggestive, it's important to take these findings with a grain of salt (so to speak). If you have a stomach ulcer and eat a lot of salt, reducing dietary salt for a couple of weeks and seeing whether the pain goes away might be worth trying. Even better, talk to your doctor as a combination of reduced salt intake and other treatments might be even more effective.

How does a high-salt diet cause stomach ulcers? 

By itself, high salt intake can cause a non-inflammatory atrophic gastritis (Bergin et al, 2003). Concentrated salt strips off the mucous bilayer by inducing edema, increasing the percentage of replicating cells susceptible to mutagenesis, and exposing the underlying epithelial cells to damaging stomach acid (Charnley and Tannenbaum, 1985). The heightened cell turnover especially in combination with mutagens increases the chances of a cancer-causing mutation occurring. Acidic damage reduces production of mucus and acid required for digestion, with chronic damage resulting in low stomach acid (hypochlorhydria) (Cromer et al, 1949) and predisposes to ulcer formation. 

Like salt, H. pylori can induce atrophic gastritis in and of itself, while also inducing an inflammatory response. However, it seems that a combination of H. pylori infection and a high-salt environment leads to a much greater chance of developing stomach ulcers and/or cancer. Damaging the mucous bilayer with salt enables H. pylori to directly contact the epithelial cells. Low stomach acid allows H. pylori to more easily survive in the stomach, especially in parts prone to ulceration/cancer such as the corpus. Inflammation generates reactive oxygen species that damage the DNA of epithelial cells, resulting in immediate reduction in function as well as debilitating mutations. Reactive oxygen species generate mutations in the cells lining the stomach that are then enriched by heightened cell turnover. Most mutations result in reduced cell function, which often shows up as cells that produce less mucus or less gastric acid on a permanent basis. However, some mutations are in genes that when damaged result in the cells reproducing at an inappropriately increased rate, oftentimes producing cancer. 

A high-salt environment also seems to induce physiological changes in H. pylori that enable the bacterium to survive under the unusual conditions. When the salt concentration in the stomach increases above a certain level, H. pylori becomes stressed and its growth slows. It changes its shape from its regular spiral to an elongated filamentous form (Gancz et al, 2008). Virulence factors (e.g. cagA, vacA, adherins) may be induced depending on the strain of H. pylori present, which enable the bacterium to invade the cells lining the stomach (Loh et al, 2007).

What constitutes high salt? Charnley and Tannenbaum (1985) stated that frequent consumption of foods rich in salt such as soy sauce (18%), dried fish (20%), and pickles (13-25%) would probably lead to increased gastric cell proliferation. Chips and pretzels are similarly salt-rich, and in large and regular amounts would be expected to have similar effects on the gastric lining. The best measure of whether you are taking in too much salt is by having your doctor measure your 24 h urinary sodium output (Sonnenberg 1986).

Stomach ulcers result from an imbalance between destructive factors such as high salt intake and H. pylori infection, and constructive factors such as the mucus-stimulating ability of prostaglandin E2 and Vitamin U. Taking Vitamin U in the form of fresh vegetable juice or supplements will to some extent counteract the negative effects resulting from high salt consumption by rebuilding the protective mucous bilayer lining the stomach. Recall the pioneering cabbage juice studies of Cheney from 70 years ago (more). The role of H. pylori infection was unknown at the time, yet cabbage juice in the absence of supporting antibiotics was effective in healing peptic ulcers. 

Whatever means you take to treat your stomach ulcer, it would be wise to reduce exposure to the causative agent(s), whether that be infection with Helicobacter pylori, NSAIDs, a stressful job, the morning donuts, or in this case, a high-salt diet. If you have stomach issues but are not sure what condition you have, visit your doctor for a diagnosis. 

Please don't treat stomach cancer with vegetable juice or Vitamin U supplements. The primary role of nutrients is to promote good health and reduce the risk of developing cancer in the first place. Once a cancer has formed, it should be treated with chemotherapy, radiation and/or surgery. 

Vitamin U may help combat the ulcergenic effects of NSAIDs

Summary - Taking NSAIDs increases the risk of you developing stomach ulcers by inhibiting your natural protective system. There are several measures you can take to help get rid of stomach ulcers due to NSAIDs -

    1) reduce the dose

    2) change the NSAID to one less irritating 

    3) counteract with other drugs

    4) switch from NSAIDs to other pain relievers

    4) take Vitamin U

Vitamin U in the form of fresh vegetable juice or supplements can be used in combination with other measures to combat ulcers. However, Vitamin U will not counteract all of these negative effects as NSAIDs are powerful drugs. If you have an ulcer and are taking NSAIDs, talk to your doctor as there may be a solution.

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Stomach ulcers result from an imbalance between protective and destructive factors. There are several destructive factors including infection with Helicobacter pylori, overproduction of stomach acid, overeating salt, alcohol and sugar, and taking NSAIDs. Ulcers often result from a combination of these factors. The focus of this post is the role NSAIDs play in causing your ulcer.

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are widely used to reduce pain and inflammation. The most commonly taken NSAIDs are aspirin (e.g. Bayer), ibuprofen (e.g. Advil, Motrin), naproxen (e.g. Aleve), mefenamic acid (e.g. Ponstal), diclofenac (e.g. Voltaren), piroxicam (e.g. Feldene). A more complete list is linked here.

NSAIDs reduce inflammation and pain by inhibiting the enzyme COX-2. COX-2 is part of your body's inflammatory response. A certain amount of inflammation is good and necessary for healing. However, too much inflammation causes pain and further damage, which is why we take NSAIDs.

How do NSAIDs cause stomach ulcers? 

In addition to inhibiting COX-2, NSAIDs also inhibit the related enzyme COX-1, albeit to a lesser extent. COX-1 catalyzes the same reaction as COX-2, that being the synthesis of prostaglandins from arachidonic acid. However, COX-1 and COX-2 have different functions due to their different expression patterns. COX-1 is expressed throughout the body continuously, in contrast to COX-2 which is only expressed during inflammation. In the gastrointestinal tract, the continuous production of prostaglandin E2 catalyzed by COX-1 stimulates mucin production. Mucin forms a mucus bilayer in the stomach that protects the lining against corrosive agents such as stomach acid. The inadvertent inhibition of COX-1 by NSAIDs reduces mucin production, leaving the stomach wall vulnerable. To compound the problem, NSAIDs also have a multitude of other negative effects including increasing the production of stomach acid and increasing oxidative stress (Matsui et al, 2011), which for people with an ulcer will cause more discomfort and make the ulcer worse.

Fortunately, not all NSAIDs inhibit COX-1 equally. Some NSAIDs are more ulcergenic than others. For example, some of the early NSAIDs like aspirin are notorious for upsetting the stomach. More recently, scientists have developed NSAIDs that don't inhibit COX-1 as much as their predecessors and while still inhibiting COX-2 strongly, so-called COX-2 inhibitors, e.g. celecoxib (Celebrex). Consequently, these newer NSAIDs may reduce ulcer formation while still providing pain relief elsewhere in your body. If you have an ulcer and are taking NSAIDs, talk to your doctor about alterative NSAIDs. Be warned that these new generation NSAIDs are not without other side effects.

 

Can Vitamin U help?

The short answer is probably. Vitamin U is a naturally-occurring nutrient found in all vegetables, fruit and grains. One of its functions is to stimulate the secretion of mucin onto the walls of the stomach. How it does this is not well understood, but it is doesn't seem to have anything to do with COX-1/2 and prostaglandins. As a result, Vitamin U can be used to counteract the mucus-depleting effects of NSAIDs.

Are there any studies supporting the use of Vitamin U to counteract the ulcergenic effects of  NSAIDs?

Yes. In 1993, Salim reported the findings of a clinical trial in which Vitamin U was found to accelerate healing of patients hospitalized for erosive gastritis (bleeding from the stomach) caused by NSAID intake. Erosive gastritis is a common precursor to stomach ulcers. The majority of the patients had been taking NSAIDs for either osteo- or rheumatoid arthritis for less than 3 months. The NSAIDs used included diclofenac, piroxicam, mefenamic acid, naproxen and ibuprofen. The double-blind study found that the patients who received 4 x 500 mg of Vitamin U (DL-methylmethionine sulfonium chloride) per day had significantly less bleeding than the negative controls. Similarly to Vitamin U, patients given the sulfhydryl amino acid L-cysteine were also found to have significantly reduced bleeding, demonstrating the action of Vitamin U is likely via its conversion to a sulfhydryl. Endoscopies performed two days after treatment revealed significantly greater healing in those who were given either Vitamin U or cysteine. Of the 57 patients who were not treated with either Vitamin U or cysteine, 4 died from their condition. In contrast, there were no fatalities in those who were treated with either of these compounds. 

Currently, it is standard medical practice in cases of erosive gastritis to get the patient to stop taking NSAIDs, or at least take less irritating types, and/or to suppress stomach acid production. For a person who is taking NSAIDs for arthritic pain, reducing the amount of NSAIDs taken is clearly not desirable. Switching to less irritating NSAIDs is an option. Talk to your doctor.

Suppressing acid production will reduce irritation of the stomach, but at what cost? Unless you are producing too much stomach acid (a rare condition), reducing stomach acid will have side effects. The major role of stomach acid is to digest protein in our food. Dietary protein must be unraveled then enzymatically chopped up by pepsin to produce peptides. Without an acidic environment, protein passes through to the duodenum half digested. Enzymes in the duodenum that further digest protein into tiny peptides or amino acids can only do so much, leaving a significant portion of protein to pass into the colon. Consequently, low stomach acid can result in inadequate protein absorption as well as colonic fermentation (smelly gas). Furthermore, long-term suppression of stomach acid production promotes the growth of Helicobacter pylori, a known carcinogen (more).

While the results of this clinical trial are promising, Vitamin U is not infinitely powerful. There is only a certain amount Vitamin U can do to reverse or prevent damaged induced by NSAIDs. Large doses of NSAIDs will probably damage the stomach faster than Vitamin U can reverse this damage. However, these findings suggest that Vitamin U may be of some use in counteracting some of the negative effects caused by NSAIDs. Drinking freshly-made vegetable juice on a daily basis provides Vitamin U as well as other beneficial nutrients such as folate. 

Vitamin U and acne, dandruff and eczema

Acne, dandruff and eczema are skin conditions the origins of which are often idiosyncratic and mysterious. However, one characteristic shared by all three conditions is low glutathione levels. Glutathione is by far the most important antioxidant in the human body, yet we absorb little of it from our food- that's why our body makes it. 

There are three main causes of low glutathione - 

1. A medical condition that drains large amounts of glutathione

2. A genetic block that prevents the biosynthesis or regeneration of glutathione

3. Not enough glutathione precursors in our diet

Identifying the root cause of your skin condition is an important first step in the healing process. However, this is easier said than done. Often we just don't know why these conditions happen. Sometimes they can break out suddenly and worsen quickly, particularly under stress. At other times, symptoms can persist chronically for years.

Irrespective of the root cause, restoring your glutathione levels is a vital part of this rebalancing act. Glutathione is a tripeptide comprised of cysteine, glutamate and glycine. Of these amino acids, cysteine is most commonly in short supply. If glutathione levels are low due to dietary factors, it is usually due to a shortage of cysteine. Cysteine is found in protein, especially that derived from animals. Cysteine is also made from methionine, again abundant in animal proteins. These sulfur amino acids are also plentiful in grain proteins. However, some people find that meat/dairy/grain are inflammatory for other reasons like hormones or allergens. 

Vitamin U is S-methylmethionine, a soluble nutrient abundant in vegetables and fruit that is converted into methionine by the enzyme BHMT2. There have not been any direct studies into whether Vitamin U has any effect on these three conditions, whether taken internally in the diet or as a supplement, or when applied topically as an active component of a lotion. However, taking Vitamin U can help restore glutathione levels which are low in the tissues affected by acne, dandruff and eczema, so it is quite likely that increasing your intake of Vitamin U will help with these conditions, especially in combination with the identification and removal of triggers of these conditions in you. 

A glass of freshly-made vegetable juice every day is an excellent way to boost your Vitamin U intake along with a slew of vitamins and minerals essential for good skin health.

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

1. Finkelstein (1990) https://pubmed.ncbi.nlm.nih.gov/15539209/
2. Mudd and Poole (1975) https://pubmed.ncbi.nlm.nih.gov/1128236/
3. Benevenga (2007) https://pubmed.ncbi.nlm.nih.gov/17413090/
4. Bertolo and McBrearity (2013) https://pubmed.ncbi.nlm.nih.gov/23196816/
5. Olszewski (1989) https://pubmed.ncbi.nlm.nih.gov/2930611/
6. Reed (2008) https://pubmed.ncbi.nlm.nih.gov/18442411/
   
7. Filipcev (2018) https://pubmed.ncbi.nlm.nih.gov/29596314/
8. Dai (2020) https://pubmed.ncbi.nlm.nih.gov/32503840/