Methylation & The Methionine Cycle
About Methylation And The Methionine Cycle
The methionine cycle is one of the center pieces to what some call the methylation pathway. The methionine cycle is really one of many pathways that make up the methylation pathway related cycles. It is helpful for us to examine all these pathways in conjunction as an interconnection of many different biochemical cycles. All of these cycles are inter-dependent on each other and the separation is really only in our minds as a way to conceptualize the process. The actual way we depict them as independent cycles is purely to help us categorize, visualize and understand them. They are really all one large cycle. A friend of mine likened it to a celtic knot. I thought that was very apt. Ultimately the body is dependent on these cycles working as a cohesive whole for us to be able to function in a "normal" fashion. Below, I will talk about methylation from a variety of points of view. I will explain what methylation is. We will examine the parts of the methylation pathway cycles which will include the methionine cycle below, the folate cycle, the transulfuration cycle, the neurotransmitter(BH4) cycle and the urea cycle will be in seperate articles as I write them. We will also examine genetic polymorphisms that can cause issues in these cycles. After I draw diagrams of each cycle and explain those cycles, I will then create a map of all of the cycles together and how they interact to create the grand Methylation cycle pathway. I realize this information is a bit scientific, and overwhelming for some. When data seems to be a bit scientific, I will begin the topic with short, easy descriptions, which will be titled (Easy Peasy in a Nut Shell Explanation). When you see that, you will know I am giving a brief, easy to understand description of the more complicated sicintific definition which will follow.
This is a list of parts of the methylation pathway that will be available with links this winter.
Methionine cycle (currently found below)
About Methylation And The Methyl Group
Methylation is a biochemical reaction in our body that is involved in many important bodily processes. It occurs more than one billion times per second in our cells. Although it occurs in all the cells of the body, 85% of methylation takes place in the liver.
Methylation invoves the removal of a methyl group from one substance, and the addition of the methyl group to another substance. This happens repetatively in various chemical reactions.
A methyl group is one carbon atom attached to 3 hydrogen atoms “CH3". A carbon can actually bind to 4 other atoms. This means a methyl group has one unbound area. This area can attach and deattach from other molecules. This process of attachment of a methyl group is called methylation. The methyl group can be transfered onto amino acids, proteins, enzymes and DNA in every cell, and all the tissues in all the organs of the body. This process is catalyzed by a variety of enzymes in the body.
Where Do Methyl Groups Come From
They can come from ingestion of food or supplements. The supplement SAM or SAM-e is a methyl group donor. You can also ingest nutrients that are essential to activate the amino acid methionine into SAM or recycle methione back to SAM once it donates its methyl group.
The body makes methyl groups and recycles them. S-Adenosyl Methionine (SAM) commonly donates a methyl group for reactions. The methyl group on methionine is used for adding methyl groups to numerous kinds of molecules, but only after methionine has been activated. Methionine's methyl group is activated by by ATP or adenosine triphosphate when adenosine is added to the sulfur of methionine to form S-Adenosyl Methionine (SAM). Once the methyl group from SAM has been donated, S-adenosyl-homocysteine can continue through what is called the methionine cycle to be recycled into an activated SAM again.
We talk about methyl groups being donated to a substrate. Substrates that methyl groups are donated to include nuerotransmitters/hormones, immune cells, DNA and RNA.
The enzymes needed for methylation are N-, and S- methyl-transferases. The cosubstrate used is the S-adenosylmethionine (SAM).
Lets look at why we need methylation.
Basic Methylation Functions
Easy Peasy In a Nutshell Explanation
Methylation is involved in most reactions that take place in our body. As I mentioned above it takes place billions of times per second in our cells, and happens more in the liver than any other organ. Where we use the most methyl groups is in the production of creatine and phosphotidylcholine.
An easy way to understand how methylation can effect us is to examine coffee. Coffee has a lot of methyl groups. Think about how coffee effects you, and you will know one way of how methyl groups can effect you personally. Some folks have to have their coffee in the AM to wake up, be able to wipe away some brain fog, be able to focus, articulate their thoughts, etc. Methylation is involved in most of our body processes. Methylation will help our immune system protect us, help us focus our attention, support nerve transmission, help us detox, and keep our energy flowing. Methylation can turn genes on, and off in our body, which can be delightful or lead to problems. For some specific details read on...
Some Important Processes That Need Methylation
- Production of energy (ATP via Krebs cycle, CoQ10, carnitine, creatine)
- DNA synthesis, and histone Synthesis (Thymine aka 5-methyluracil), repair & expression of DNA (turning genes on and off), RNA synthesis, regulating protein function,
- Modification of toxins and chemicals. Processing of both endogenous and xenobiotic compounds for removal from the body (biotransformation via Phase II liver clearing)
- Glutathione production which is very important in biotranformation/detoxification
- Ability to methylate modulates neurotransmitter function. Need it to build neurotransmitters such as dopamine, and epinephrine as well as degradation, or catabolism/breakdown of these neurotransmitters.
- Making and processing hormones
- Building immune cells (T cells, NK cells)
- Building and maintaining cell membranes (phosphatidylcholine). This is via utilization of phosphatidylcholine derived from phosphatidylethanolamine in the presence of functioning PEMT enzyme.
- Building myelin which is a protective insulation on nerves. and to inactivate histamine.
How You Are Effected by Methylation
- Mutations in the methyl transferase genes cause serious, sometimes lethal, defects. It is known that environmental conditions affect methylation and that methylation degrades with age. Several of the diseases of old age, including diabetes and Alzheimer’s, are known to be associated with aberrant patterns of methylation.
- In people with decreased activity in the methionine cycle there is a shortage of activated methyl groups in the body needed to execute many important bodily functions. Additionally, varients in methylation decrease protection from environmental, and infectious agents. These methylation variables can cause a wide range of conditions including thyroid dysfunction, early aging, diabetes, cardiovascular disease, neurological inflammation, neurotransmitter imbalances, chronic viral infection, atherosclerosis, cancer, schizophrenia, decreased repair of tissue damage, improper immune function, neural tube defects, Down’s syndrome, Multiple Sclerosis, ADD, ADHD, Alzheimer’s, autism, Huntington’s disease, Parkinson’s disease.
- Genetic varients in the methionine pathway, and methylation can cause susceptibility to health conditions. In addition, DNA methylation can cause epigenetic modification. Methylation is involved in how the genes respond to environmental triggers.
- Problems in the methylation pathway can reduce the bodies ability to make the building blocks (purines and pyrimidines) needed for new DNA, and RNA synthesis. Some of the bodies cells are more susceptible to these methylation issues such as the bone marrow which makes platelets, white blood cells, and red blood cells. Neural tissue is also more likely to be effeted.
- Problems in methylation can effect the mitochondria in our cells. Mitochondria are the units that create energy in our cells and ultimately allow all the cells to function. Mitochondria need key nutrients/coenzymes dependent on methylation to be able to create energy. Their basic fuel is derived from glucose or fatty acids from triglycerides. However, they also need a variety of nutrients to function.
Aging and Methylation Effects
Easy Peasy In a Nutshell Explanation: As we get older methylation does not work as well, and causes many diseases we associate with aging.
Scientific Data: Gene expression changes during development and maturation, and it is possible that this is accomplished through changing methylation patterns. Gene expression is known to change at advanced ages. These changes may be random, and haphazard, or programmed and determined. The current hypothesis is that altered patterns of methylation may be a cause of the disabilities and altered metabolism that come with age.
- DNA methylation declines with age, resulting in cellular dysregulation. In general, we lose more methylation activity than we gain over time. In research, DNA from older animals is less methylated than from young animals, though there are also some regions of the DNA where there is more methylation with age. In one human study (Bollati 2009), their results on an elderly population in Boston showed a gradual decrease through aging in repetitive element DNA methylation, particularly in Alu sequences. Both animals and people with less total methylation are prone to a variety of age related disease. (Fraga, 2005).
- In the Fraga study, gene methylation patterns were compared in identical twins when they were very young, and when they were older. Methylation patterns were very similar in young twins, but diverged markedly over time indicating a possible epigenetic alteration. Other evidence indicates that relatively small differences in epigenetic patterns can have a large impact on physiological traits. One hypothesis is that some of the body’s loss of function with age has to do with the difference in the way that methylation changes over time. (since I wrote this article many epigenetic factors have been found to alter methylation)
Biotransformation/Detox Effects Of Methylation
Easy Peasy In a Nutshell Explanation: Taking a chemical from the environment, or from our body that could be harmful and transforming it into something that is less harmful that can be removed from the body or stored out of the way is called biotransformation, or detoxification. Methylation is involved in this process.
Scientific Data: This process involves conjugating (combining) methyl groups to the toxins prior to removal, as well as, supporting the production of glutathione and metalloproteins. Most of the methyl groups used for detoxification come from S-adenosylmethionine (SAM).
Methylation occurs when SAM (S-adenosine methionine) donates a methyl group, which is then attached to the molecule that is being detoxified. SAM then becomes S-adenosine homocysteine.
Hypermethylation as well as hypomethylation is associated with a large number of human cancers. Normalization of methylation is important in cancer prevention and is being researched for cancer treatment. Reduced DNA methylation results in genetic instability, aberrant gene expression, and increased cancer. Hypermethylation can also be associated with human cancers.
Folate deficiency has been implicated in the etiology of lung, cervical, breast and brain cancer. Convincing evidence links folate deficiency with colorectal cancer incidence. Colorectal cancer incidence is inversely associated with both dietary folate intake and blood cell folate concentrations. Supplementation of folate to prevent colon cancer has had varied results and may have something to do wtih folic acid (synthetic form) being used in the research rather than folate. More research is needed.
Cell Membranes & Membrane Fluidity
Easy Peasy In a Nutshell Explanation: Every cell in your body depends on methylation for its outside wall to be able to maintain strength and flexibility. Without methylation the cells membrane can not function well.
Scientific Data: Methylation is needed to build and maintain cell membranes. Methylation is necessary in making phosphatidylcholine that is used in making the cell membrane.
Our cell memrances need to have fluidity. The membrane fluidity allows it to be mobile as it protects the cell from negative outside influences or decides to let needed nutrients inside. This fluidity is dependent on the phospholipid membrane that incorporates phosphatidylcholine.
Overtraining is an issue. Creatine needs SAM for it's methyl group. The more muscle mass you have, the more creatine you need, and the more SAM you need to make it. Creatine, and phosphotidylcholine use up the majority of SAM in body. Creatine is about 70% of SAM use.
DNA & RNA
Easy Peasy In a Nutshell Explanation: Methylation is a part of RNA, DNA creation, activation, silencing and repair. Methyl groups are important in control of gene expression. Genes can be turned on and off through DNA modification. Methyl groups (as well as some other molecules) can attach to the DNA sequence which will prevent, or promote expression of the genes nearby. They help turn your genes on (express the gene) and off (silences the gene). I have seen some people refer to this in relation to a charm bracelet and I think that analogy is really helpful. Think of your DNA as the chains of a charm bracelet, and the methyl groups are the charms that can be added to the bracelet. The very charm bracelet itself is dependent on proper methylation to create the proper DNA to build the bracelet. (This can be effected in utero.) The charms on the bracelet are the methyl groups. You can add charms (methyl groups) to the charm bracelet or you can remove charms (methyl groups) from the charm bracelet.
We can think of DNA variants as changes in the bracelet chains as well as changes in the ability to make the appropriate amount of charms and add or remove those charms.
Methyl groups can combine with other compounds that instigate reactions that will activate a gene or an enzyme. When there is a lack of methyl groups you do not get the necessary activity of the gene or enzyme. Sometimes lack of a methyl group could mean that a gene is turned on also.
Abnormal methylation changes play a role in diseases, such as cancer or fragile X syndrome, and may also occur as a function of aging or as a result of environmental influences.
Genetics And Epigenetics
So we have seen above that methylation can control gene activity. In addition, various genetic mutations or what is also called variations, can affect methylation. A common genetic variation is the inability to create active folate from dietary folate. 40% of the population has this genetic variation that limits partially or completely the ability to process dietary folate into active folate due to a single nuceotide polymorphism (SNP) variation. This variation will decrease the activity of the methylation cycle which can effect DNA replication which can create an unhealthy cycle.
Genetics are useful, but epigenetics are generally as important and may even be more important than the genetics themselves. Lifestyle and diet make all the difference in the world. Eating appropriately, living in a non-toxic, non-stressful environment are key ingredients to adequate methylation. Genetics becomes more important when you come from a family that tends to die early or have a lot of chronic illness. Genetics becomes more important in pregnancy and in aging also.
Scientific Data On Folate And DNA Stability
Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydrofolate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer. Moreover, folate effects gene expression by regulating cellular S-adenosylmethionine (SAM) levels. 5-Methyltetrahydrofolate serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to SAM. SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer. There is convincing evidence that folate modulates both DNA synthesis and repair and DNA hypomethylation with altered gene expression in vitro.
Cells produce energy in the mitochondria which is often called the cellular power house. Mitochondria produce energy to run the body. This energy is called adenosine tri phosphate (ATP). The methylation cycle products are a part of what empowers the mitochondria. Carnitine and CoQ10 which are both dependent on the methylation cycle are needed for mitochondria to function properly. Without energy you get really tired, and you experience muscle pain and generalized inflammation along with other symptoms.
Exercise and Methylation
- Chronic moderate exercise appears to attenuate the age-dependent decrease in ASC gene methylation.
- High intensity exercise has been shown to result in reduced DNA methylation in skeletal muscle.
Caffeine could induce the same changes in DNA methylation as exercise. Calcium is stored in compartments in each muscle cell, and when it gets released this signals the muscle cell to contract. Bathing a muscle cell in caffeine will cause it to release its stored calcium, effectively causing muscle contraction. The researchers bathed the cells in caffeine to cause contraction, and trick the muscles cells into thinking they were exercised. This resulted in a decrease in methyl groups on the same genes as before, causing increased expression of genes that support sugar and fat metabolism.
This in vitro research doesn’t mean that we can all drink coffee, or other caffeine drinks/foods as a substitute for exercise and get the same results. Even if we could, the amount of caffeine used to bathe the cells in these experiments is equivalent to 50-100 cups of coffee!
People with type II diabetes have more methyl groups on the metabolic genes compared to people without type II diabetes, and this worsens their metabolic response to sugar, and fats because their genes are turned off. The researchers hypothesize that exercise may be a way to remove the methyl groups, and restore the proteins and enzymes to help control metabolism of sugar and reduce the symptoms seen in type II diabetic patients.
The gut houses about 3 lbs of friendly gut bacteria that is very important to our assimilation of nutrients needed for methylation. A large share of our immune system is located in the gut. These microbes and the immune system can have a big effect on neurotransmitter status.
Estrogen is methylated to be broken down and removed. Without methylation it can rise to excess levels.
Found in some well water, chicken as well as rice can have high levels of arsenic. Arsenic negatively affects SAM (primary methyl donor) as well as glutathione. Need both to get arsenic out of the body.
Easy Peasy In a Nutshell Explanation: The immune system needs methylation to function properly. Methylation decreases with age, thereby affecting our immune system. It appears that impaired methylation can create an inflammatory state and is a factor in autoimmune conditions.
Scientific Data: Problems in methylation can affect the immune system. As mentioned above, you may have trouble making the building blocks that are needed for new DNA synthesis. If you cannot make new DNA, then you cannot make new T cells and as a result you may lack immune system regulatory cells. T cells are involved in protecting us from viral and parasitic infections as well as controlling B cells which produce antibodies. When the methylation pathway is not working well, the immune system will have an increased tendency to make B cells, which may result in an autoimmune disorder. Methyl cycle supplementation has been used in treatment of autoimmune disorders when related to underactive methylation.
Methylation is also involved in building natural killer (NK) cells.
As we age, methylation decreases. This can cause a decrease in T cells and NK cells which can change immune system function.
Methylation plays a role in the ability of the immune system to recognize antigens (foreign bodies) that it needs to respond to. Research has shown that methylation is decreased in humans with auto immune conditions. DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Research with DNA methylation in T cells has shown abnormal DNA methylation plays a role in idiopathic human lupus. Methylation may also affect the balance of TH1/TH2 (Helper cells in immune system). Methylation impairment may lead to alteration of TH1/TH2 and create an inflammatory state.
Easy Peasy In a Nutshell Explanation: Poor methylation and inflammation are found hand in hand. They feed off each other. If you have one, you have the other.
Scientific Data: Poor methylation produces inflammation and inflammation decreases the ability to methylate adequately. So, you can get a continuous feedback loop.
More inflammation tends to lower methylation. IL6 and TNF alpha are two biochemical markers that are high in inflammatory states. When these are high, they tend to lower methylation status.
When methylation is low, histamine levels tend to be high. Histamines are deactivated by receipt of a methyl groups. Histamines are released in response to antigens and are linked to inflammation..
Inadequate methylation is associated with autoimmune disorders.
Easy Peasy In a Nutshell Explanation: S-adenosylmethionine (SAM) is the queen of methylators. Morphine, cow milk protein, and a wheat protein were all examined and found to decrease SAM significantly. This would significantly decrease methylation in the body. Cow milk protein lowered SAM, but human milk protein did not.
Scientific Data: Review of research - Epigenetic programming, including CpG methylation and histone modifications, occurring during early postnatal development can influence the risk of disease in later life, and such programming may be changed by nutritional factors such as milk, and wheat, especially during the transition from a solely milk-based diet to one that includes other forms of nutrition. The hydrolytic digestion of casein (a major milk protein) and gliadin (a wheat-derived protein) releases peptides with opioid activity. This study demonstrated that these food-derived proline-rich opioid peptides modulate cysteine uptake in cultured human neuronal, and gastrointestinal epithelial cells (cells lining gut) via activation of opioid receptors. Decreases in cysteine uptake were associated with changes in the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine.
Morphine and exorphin peptides caused progressive decreases in reduced glutathione/oxidized glutathione, reaching more than 3-fold at 24 h (P<.01, Fig. 2a). Morphine, bBCM7 (cow milk protein) and GM7 (wheat protein), but not hBCM7 (human milk protein), transiently decreased SAM/SAH, with a 2–3-fold reduction of SAM/SAH levels observed with morphine, bBCM7 and GM7 treatments at 24 h (P<.01). Thus, the decrease in cysteine uptake caused by morphine, and opioid peptides translates into downstream changes affecting redox status, and methylation capacity in research with human neuroblastoma cells.
Nerves carry their messages from one neuron to another or to other tissues in the body. Nerves can be compared to an electrical wire. Just as an electric wire is usually insulated to protect it, and help it to carry the electricity from your electric box to your light bulb, the bodies nerves also need insulation to protect them. This insulation on nerves is called myelin, and myelination is the act of putting this insulation on the nerves. Methylation is involved in proper myelination. Lack of proper myelination is associated with a variety of health conditions. Sometimes there are antimyelin antibodies in the body. Inflammation is usually associated with antibodies against our own body and methylation inadequacy is associated with inflammation.
Nerve Health, Excitotoxins & Methylation
Excitotoxins are toxins that are created in the body, or that are from our environment. Excitotoxins are added to the food supply as flavor enhancements. They include such additives as monosodium glutamate, hydrolyzed vegetable protein, and aspartame. Glutamate or glutamine is also found in some nutritional supplements. Although excitotoxins are found naturally in the body such as glutamate, it is in very low concentrations. Excitotoxins found in food can over-excite the nerve cells. They become inflamed and may fire so fast they become exhausted or even die. People with a genetic variation that causes susceptibility to glutamate or other excitotoxins need to be aware of these additives and food supplements.
Body glutamate can rise when there is inadequate methylation. If the methylation pathway is not working fully, folate (a polyglutamate) is not used in the pathway properly, and it can break down into glutamate. The body deals with excess glutamate by increasing glutamate receptors which has been shown to correlate to higher intelligence. So, although there can be neuron inflammation and even damage due to high glutamate, you may also see increased intellect.
S-adenosylmethionine (SAM) brings methyl groups to numerous chemical compounds in your body. It creates neurotransmitters such as dopamine, and norepi/epi as well as changing or degrading neurotransmitters. If we don’t have enough SAM, or if SAM can’t be recycled due to an inadequate methylation cycle, this can result in imbalances in our neurotransmitters. This impacts a wide range of behaviors, mood, ability to focus attention and sleep.
When methylation is inadequate a person can not make the necessary components needed to generate neurotransmitters like serotonin, which regulates mood, emotion, and appetite, as well as problems converting serotonin to melatonin, which allows us to sleep at night.
Proper dopamine signaling requires that the dopamine receptor be able to move freely within the cell membrane. The dopamine receptor, located on the cell surface, is like a fishing pole that catches dopamine. Methylation supports receptor mobility by keeping the phospholipids in the cell membrane fluid. Membrane fluidity also aids proper signaling of the immune system and protects nerves from damage.
Stress increases cortisol which increases methylation. Ongoing stress pushes methylation all the time, and means you need to produce more methyl donors. You need leafy greens to support the methylation cycle, and stress often induces people to eat more carbohydrates, and less leafy greens, which means you are using up methyl donors and not making enough of them.
Epinephrine, and norepinephrine are increased from stress, and need SAM (methyl group) to convert norepinephrine to epinephrine.
Put diagram here of SAM to dopa to epi etc.
If one is hypothyroid, and thyroxine (T4) levels are low, combined with low riboflavin status, then the MTHFR enzyme will function more slowly even if there is no MTHFR mutation/defect. You need thyroxin (T4) to convert the b2 into the active Flavin Adenine Dinucleotide (FAD) needed to assist the enzyme MTHFR in making 5-mthf (as well as glutathione by the way and many other things.)
Specific Health Issues Related to Methylation Disorders
Methylation plays a role as primary or related role in all health disorders. Methylation is taking place in all cells of your body at all times.
- Addictive Behaviors
- Alzheimer's Disease
- You see increased homocysteine in Alzheimer's Disease. Cerefolin (5methylfolate drug) is used to target the treatment of dementia in Alzheimer’s patients at a 5.6 mg pill dose.
- Aromatase Excess may be related to decreased methylation. Research has noted this correlation in breast adipose tissue. Need more research.
- Attention deficit disorder
- Ritalin is also a methyl donor and therefore helps children with low methylation status improve their attention span.
- Bipolar Disorder
- Bowel dysfunction - Bowl dysfunction is related to the low T cells seen with methylation problems. This can lead to elevated B cells, leading to auto-antibodies such as seen against gluten (wheat) and casein (milk). Additionally when methylation is low and T cell production is low, then histamine levels tend to be high. Histamine is linked to inflammation and inflammation in the gut can cause "leaky gut".
- Reduced DNA methylation results in genetic instability, aberrant gene expression, and increased cancer — although high methionine intake may increase cancer in different ways than low methionine intake.
- Cardiovascular disease
- As we age, methylation decreases. This causes an increased level of homocysteine which is a risk factor for cardiovascular disease. Carnitine and CoQ10 are lacking with poor methylation and they are needed for proper heart function.
- Decreased BH4 is seen with hypertension, atherosclerosis and endothelial dysfunction.
- Cervical Dysplasia
- Chemical Sensitivity
- Chronic Fatigue Syndrome
- Chronic bacterial/viral infections
- Cleft Palette
- Congenital Heart Defects
- Decreased repair after tissue damage
- In a diabetic state there is increased expression of specific methyltransferases that utilize SAM derived methyl groups and produce homocysteine. Although the supply of methyl groups from the folate-dependent 1-carbon pool appears to be diminished under diabetic conditions, the increased production of homocysteine is compensated for by stimulation of folate independent remethylation, and catabolism by transsulfuration, resulting in hypohomocysteinemia.
- You see decreased BH4 in diabetes.
- DNA Dysfunction
- The ability of Polychlorinated biphenyls (PCBs) to reduce DNA methylation in animals may also be reflected in humans.
- DNA Repair Impairment
- Down's syndrome
- Downs syndrome is linked to specific methylation mutations/variations in methionine synthase, methionine reductase and elevated homocysteine.
- Heavy metal toxicity
- Huntington's disease
- Immune Deficiency
- Leaky gut: Involved in protecting the intestinal lining.
- Mitochondrial disease
- Multiple Sclerosis
- Neural tube defects
- There is now common acceptance of the association with inadequate methylation being a risk factor for neural tube defects. Elevated homocysteine concentrations have been observed in mothers who have delivered children with an NTD but who have normal folate levels, which was taken as an indicator of dysfunction of folate metabolism. The strong homocysteine-lowering effect of folate supplementation indicates that this form of dysfunctional folate metabolism can be overcome by additional folate intake.
- Mothers who are homozygous for the MTHFR 677C>T variant (677 TT) have a 60% increased risk of giving birth to an infant with an NTD, whereas homozygous offspring themselves have a 90% increased risk of being born with an NTD. Furthermore, we also found a 10% increased NTD risk in mothers and 30% increased risk of offspring who are heterozygous for the MTHFR 677C>T variant (677 CT).
- The 677C>T polymorphism (which leads to substitution of Ala by Val at amino acid number 222) results in the loss of flavin adenine dinucleotide (FAD) from MTHFR. Folate binding to MTHFR prevents this loss. Riboflavin (vitamin B2), which is a precursor of FAD, lowers homocysteine concentrations in individuals with the 677 TT genotype, which indicates that, in addition to folate, it could be important to investigate riboflavin intake in relation to the prevention of NTDs. (Blom, 2006)
- Additionally, the 677 TT genotype results in a global reduction in the methylation of DNA. (Friso,2002) This does not sound like good news.
- The methionine synthase reductase (MTRR) 66A>G variant has emerged as a possible genetic risk factor for NTDs. Other potential candidates are the MTHFR 1298A>C, methylene-tetrahydrofolate dehydrogenase (MTHFD) 1958G>A and transcobalamin 776C>G variants. (Linden, 2006)
- If a woman's MTHFR enzyme is missing, the final product it would usually produce can be given as a supplement. This would be 5-MTHF. Additionally, riboflavin (also known as vitamin B2), which is a precursor of FAD, lowers homocysteine concentrations in individuals with the 677TT genotype, which indicates that, in addition to folate, it could be important to investigate riboflavin intake in relation to the prevention of NTDs.
- The inhibition of methylation is a factor for the b12 or cobalamine deficiency-associated neuropathy.
- Neurological inflammation
- Excitotoxins such as monosodium glutamate, hydrolyzed vegetable protein, and aspartame found in some food products can overexcite the nerve cells. They become inflamed and may fire so fast they become completely exhausted or may die.
- One of these excitoxins that is also made in the body called glutamate, can also rise when there is inadequate methylation. If the methylation pathway is not working fully, folate (a polyglutamate) is not used in the pathway properly and it can break down into glutamate.
- Neurotransmitter imbalances
- You see decreased dopamine and serotonin with decreased BH4.
- Parkinson’s disease
- Prenatal caffeine ingestion: Various research studies have shown that caffeine may be associated with various in utero changes resulting from alterations in DNA methylation. These in utero changes in DNA methylation are associated with risk for developing obesity, and cardiovascular disease, (Basurto-Islas, 2014) as well as intrauterine growth retardation (Ping, 2014)
- Psoriasis - Decreased methylation has been associated with Psoriasis.
- Renal failure - Increased homocysteine is seen in renal failure. Seems to be related to BHMT pathway which is the pathway that converts homocysteine to methionine without folate. It is also called the short pathway and is only in kidney and liver. The end product is methionine and DMG. You see excess DMG in renal failure along with the rise in homocysteine.
- Rett's syndrome
- Sleep disorders: Insomnia can arise from the lack of melatonin. Methylation is necessary to make melatonin from serotonin. Serotonin is converted to melatonin by three steps involving a series of enzymes that add an acetyl, methyl and finally a hydroxyl group to the indole ring.
- Spina Bifida
- You see increased homocsysteine in stoke patients.
- Systemic lupus erythematosus
- Thyroid Dysfunction
Ecological Disturbance Causing Diseases Related To Methylation
A common question is why do we have so many methylation health issues and why are they getting worse? Why were our grandparents more immune from these methylation issues?
In my opinion it comes down to ecological disturbance. Our ecosystem can not support the high density of humans, and the things we are doing to our planet. This population explosion and dense living situation on the planet has lead to pollutants in our air, water, soil, food, homes, work places, schools etc. We are also using agricultural, and industrial methods that poison our environment and ourselves. There is a lack of understanding amongst the general population at large that these factors are causing the demise of their health. The reason these pollutants, and unhealthy lifestyle choices are causing the health issues listed above all comes down to a shared factor (not the only factor but a major factor). They all consume methyl groups. (They also use up other factors and co-factors in other parts of the biotransformation/Detox system. It is not just methylation.) I am not saying a lack of adequate methylation is the only issue, but it is a common and significant issue. Unfortunately due to epigenetic changes from our environment, many of us have genetic variants in our ability to methylate making the situation even worse. Methylation is just one of the many activities in the body that is over-worked and undernourished. I suggest examining all the biotransformational processes of our body and learning how to support them.
This comes down to both lifestyle and environmental issues. We can look at some main categories below.
Exposes us to the pollutants that get into our water, air and food. In my opinion, genetically engineered foods with their extreme use of herbicides such as glyphosate, and vegetable plants that actually make their own pesticides are one of the more frightening issues on the planet. They are quietly destroying the health of people and animals. Pesticide and Herbicide use is decreasing nutritional quality of the food, destroying the soil by killing off microbial life and chelating minerals. This creates a soil that is unfit to grow health inducing food. In fact food can become disease inducing rather than supportive of health when industrial farming is the agricultural method used. We have tossed out the healthy soil methods such as composting, crop rotation, animal rotations etc. The current industrialization of farming adds to the toxic burden on our bodies. Some chemicals such as glyphosate have been linked to decreased detoxification pathways. Methylation is one of the methods the body uses to detoxify itself. If the body is under environmental onslaught it needs more methylation products, and yet in this situation the body is unable to make enough due to a lack of nutrients available, or may simply not be able to keep up with the increased need fast enough.
Monocropping of our forests
This is one form of farming that is not usually recognized as monocropping or as an issue. We are monocropping our forests for timber. We grow monocrops of fir trees in the USA specifically. Just as when we monocrop on a vegetable, or fruit farm. Forests have an intricate web of life that is necessary for a healthy forest. The old mother trees support the younger trees and fungi help bring nourishment to the trees as well as moisture when a dry spell hits. These are just a couple examples of what takes place in a healthy forest. Mother trees and fungi are gone or incomplete in monocropped forests. Monocropping in the forest creates unhealthy soil, as well as sick trees and means a sick crop that then causes the forester to come in with chemicals to protect a sick forest from the ravages of insects (which are out of control due to lack of beneficial insects, just like happens in our gut) which are sprayed from overhead, and drifts onto nearby people as well as ends up in the water supply that we drink and the sea is dying from. Additionally, once the old growth forest is gone, there is now competition for space between the firs, and the new weeds that are growing from stirred up seed. This starts overhead herbicide spraying. This also drifts through the air to people and ends up in the water supply and sea again. These herbicides and pesticides sprayed on our forests are polluting the planet. This can negatively effect our health as well as other creatures on Earth. This type of monocropping has also set our forests up to be ravaged by forest fire. Old Growth Trees Protect Us From Forest Fires
Poor nutrition due to industrialized farming, chemicals used on food, genetically modified foods with high glyphosate use, leading to unavailable minerals, foods grown for easy transport and long shelf life, rather than nutritional content. There is also poor nutrition from food choices, and the decreased responsibility taken for ones own food. (Lack of gardening of one's own food or procurement from local organic vendors.) Vitamins necessary for enzyme activity in the methylation cycle or vitamins/minerals needed as cofactors may become unavailable, or less available due to poor farming practices, or from food that is old, and has lost quality through shipment, lack of proper refrigeration or other storage/shipping issues.
Poor nutrient assimilation
Chemicals on our food can affect nutrient assimilation by chelating them and making them unavailable. Additionally, some chemicals such as glyphosate (Round Up) have been linked to dysbiosis, and gut inflammation in research with animals (There are conveniently no studies on humans.) When your gut bugs are not available or not working up to par, and/or you have gut inflammation, you are unable to process, and absorb nutrients needed for methylation even if you are ingesting them.
Environmental pollutants to air, water, soil
- Pollutants in building products that we live, work and go to school in.
- Pollutants sprayed all over the city parks, business and apartment landscaping.
- Pollutants from industrialized farming.
- Pollutants from other industry.
- Pollutants from transportation.
- Pollutants sprayed in our forests.
- Pollutants from daily living choices.
All these environmental toxins can disrupt methylation. Additionally, mutations in the methylation cycle can create trouble in toxin excretion. See details on Toxins and Detoxification here. Excess pollutants stress the methylation pathway as biotransforming toxins requires the methylation process to work extra hard, and it may not be able to keep up, especially if there are already mutations in the genes that support the methylation cycle.
Stress of our foremothers and forefathers was different than our current stress. For them stress was usually dealt with when it came up. Now, we have chronic reoccurring stressors that many people have no control over. People have less control over their work and home environment. Things have sped up. People are often overextended and they are not replenishing themselves when they have rest time by using relaxation techniques. Many people also lack connection with nature, and spirit, which is necessary to give people a sense of connection and belonging. Most people feel a loss from not being able to reach their full spiritual potential. All of these stressors can affect methylation. Your mental/emotional state can affect methylation, as well as other biotransformation pathways. Stress, anxiety, lack of sleep can all interfere with our biotransformational pathways.
Inflammation is at the base of all chronic disease .There are a variety of instigating causes.
Examples Of Things That Cause Inflammation
Glyphosate: There is research on chemicals sprayed on our food, such as glyphosate causing decreased microbial diversity in our guts, and instigating the release of zonulin which leads to loosening of the tight junctions in the epithelial cells of the gut which is what we call "leaky gut".
Mold: Mycotoxins can cause inflammation in the gut just as does glyphosate. It also can cause inflammation all over the body by increasing inflammatory cytokines. I work with people who are susceptible to mycotoxin reactions. Mycotoxins can gain access through respiration, skin, ingestion, or any orifice of the body. These mycotoxins as well as bacterial endotoxins, and toxins from human-made materials in buildings run rampant in water-damaged buildings due to poor building practices, and use of toxic materials in our buildings. These toxins from water-damaged buildings can lead to general inflammation. Any time you have inflammation in the body it can lead to further inflammation, and like a snowball get out of control and become chronic. Gut inflammation is especially bad as when the gut is inflamed, and tight junctions are no longer tight, food particles, and toxins get through the gut into the blood along with chemicals our own body makes such as zonulin from the epithelial cells, which further causes inflammation in other areas of the body. Supporting our bodies ability to remove inflammatory instigated debris means we need to work on all areas of transformation and detoxification.
Don't worry, there are things we can do about all of this. The direction we choose to go is in our own hands.
What Factors Disturb Methylation
Methylation Can be Turned Off by the End Product
The end product of methylation can turn methylation off through feedback inhibition. When there is a lot of end product, this will cause a feedback loop to stop the methylation process that is making that end product.
DNA Mutations/Variations Effect Methylation
DNA makes the enzymes needed for methylation. If DNA is mutated (a variation) it can make enzymes that may not work or may not work as well. Genetic mutations in an enzyme that is necessary for creation of methyl groups can substantially reduce methyl group production. Additionally, genetic mutations that affect other biotransformational pathways can affect the methylation pathway. For instance if the folate pathway has a problem, and 5-MTHF is not created, the methionine pathway is then slowed down and methylation is slowed down.
Disruptions in other pathways
The methylation pathway Involves interactions between botransormational pathways we call the Folate Cycle, the neurotransmitter BH4(Biopterin) cycle, transulfuration cycle and the Urea Cycle. Although the methylation cycle is technically the methionine cycle. The methionine cycle, and all these other cycles are sometimes called the "Methylation Pathway".
All of our biotransformational pathways work in conjunction with each other, but these mentioned cycles are very closely related to each other and are discussed here as the "Methylation Pathway/Cycle".
Lack Of Substrates/Enzymes/Cofactors To Support Methylation
Decreased activity in the methylation cycle means there will be a lack of methyl groups to perform normal body functions. This makes it hard for an individual who has additional insults from the environment, parasites, viruses, heavy metals etc.
Lack of proper enzymatic cofactors such as magnesium, zinc, B6, b2, methylcobalamin.
Medications & Nutrients Or Supplements Can Disturb Methylation
These medications are listed in alphabetical order. If you notice I have not listed one that should be included, please email that data to me. (Email icon on bar at top of page.)
- Alcohol inhibits methionine synthase, depleting glutathione (GSH) in the brain & liver, and decreasing the SAM/SAH ratio.
- Antacids can deplete B12 which is necessary for methylation.
- Antimalarials JPC-2056, Pyrmethamine, Prguanil (inhibits DHRF)Carbamazepine – folate antagonist
- Bactrim inhibits Dihydrofolatereductase (DHFR)
- Cholestyramine and colestipol (Can deplete cobalamin and folate through decreased absorption if taken together with these drugs.)
- Cyclosporine A decreases renal function and increases homocysteine
- Environmental toxins such as:
- Heavy metals,
- Chemicals (acetylaldehyde which is a component of alcohol (from yeast, candida over growth, yeast create it when making alcohol)
- High copper
- these all use methyl groups and deplete them.
- Excessive substrate/Feedback Inhibition: If you have too much SAM, you won't produce more. If you take glutathione it will stop production, excessive cysteine also.
- Methotrexate inhibits dihydrofolatereductase (DHFR) enzyme (part of folic acid metabolism) now decreased methylation during whole cancer treatment and may have other cancer cells on rise due to the DNA proliferation .
- Niacin uses a lot of SAM and SAM is the main methyl donor in the body. Niacin limits pyridoxal kinase. Pyridoxal kinase + ATP --> ADP +Pyridoxal 5-phosphate (active B6) and as such is useful during times of over methylation ( (Niacin is used for high cholesterol and for blood clotting disorders.)
- Nitrous oxide inhibits methionine synthase (MS). If someone uses nitrous oxide at their dentists, you can give lots of methionine, methylcobalamin, SAMe and methylfolate before going. However, nitrous oxide is not a good idea for folks, especially if they are poor methylators. If they use nitrous, they will feel terrible and they will have very high homocysteine. When this happens, they are best helped by use of methyl folate, methyl cobalamin, betaine, tmg.
Nitrous also inhibits the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) enzyme. If they already have limited MTR enzyme, reducing it further is an issue. This enzyme makes methionine from homocsysteine. Giving homocysteine temporarily can help supply the methionine but you still have this back up of homocysteine that will clutter up the pathway.
- Mental Emotional Stress
- Metformin decreases cobalamin absorption. In a person with a methylation defect this means you are decreasing methylation even more. (metformin used in diabetes, poly cystic ovarian syndrome and endometriosis)
- Oral contraceptives deplete folate. There may be miscarriages later due to lack of folate
- Phenytoin is a folate antagonist.
- Sulfasalazine inhibits dihydrofolatereductase (DHFR)
- Theophylline limits pyridoxal kinase used to make active B6.
- Triamterene inhibits dihydrofolatereductase (DHFR)
- Your mental/emotional state can effect methylation as well as other pathways. Stress, anxiety, lack of sleep can interfere with our biotransformational pathways including methylation.
How To Address the Methylation Issues
- As a society we need to clean up our act on a social/environmental level.
- Support A Balanced Methylation Cycle
This involves the following Factors: Environmental Changes, Lifestyle Changes, Dietary/Nutritional Changes, Mental/Emotional Support, Genomic Analysis & methylation support
We will focus on genomic analysis, and methylation support here as these other issues are out of the realm of what we can cover in this article.
Genomics & Methylation
We can identify the presence of single nucleotide polymorphisms (SNPs) in the methylation pathway that can cause a person to over methylate or undermethylate. By using diet and/or supplementation we can bypass these genetic variations to optimize the methylation cycle and support the health of the individual. Over time, this will optimize the persons health and will often reduce various inflammatory issues the person is dealing with.
A tool that will be indispensable for assessing your methylation cycles function is genomic analysis. To do this, you first need a genome test which you can get at 23andMe.
Where To Get Information To Understand The Testing
Once you get this test back you can run it through software that is created to examine SNPs that are known to correlate with deficiencies or excesses in the methylation and other related pathways. You can read more about genome tests and SNPS here. You will find some links to websites near the bottom of the page that offer software programs that help identify SNPs that may be problematic and identify if they are homozygous or heterozygous. While some of these sites such as gene genie gives additional information that includes medical information, most sites do not. For lay people who have not spent a lot of time studying SNPs and the methylation pathway they will find it hard to understand these tests. However, there are practitioners who will take this data and give a report to help the lay person understand it.
Identifying Methylation Issues
Once you identify areas of your methylation cycle that are not functioning up to par, you can figure out if there are ways to help support the amount of function that currently exists. Sometimes you can support back up pathways. This may involve dietary changes or ingestion of nutritional supplements, or herbs, as well as exercise, relaxation techniques or other lifestyle changes. Often people who are seeking information on improving methylation are not feeling well and need more than methylation support. It is often necessary to start with other avenues before supporting methylation. Otherwise suddenly activating the methylation cycle full force can put strain on other pathways, and body processes that are in poor working condition. Therefore a person should have a health care professional assess their health status and review their physical, mental,emotional and spiritual well being before beginning methylation support.
SNPs Causing Issues
There are specific SNPs known to cause problems with methylation. Two of the main ones are part of the Folate Cycle which is like an arm of the methylation cycle. The two most common and well known are C677T variant and A1298C variant. These variants can effect the methionine/methylation cycle and decrease it tremendously. You will hear people talk about them as being MTHFR issues.
Methylation Support Begins with Understanding the Methionine Cycle (If you want to -For Medical biochemistry Geeks)
There are a variety of substrates needed for proper methylation. The methionine cycle is the heart of the methylation pathway where methylation products are activated. This cycle is dependent on other pathways that are connected to it, but the methionine cycle is definitely the place to start the learning process. The methionine cycle contains four substrates, methionine (MET), S-Adenosyl Methionine (SAM), S-Adenosyl Homocysteine (SAH), and Homocysteine (HCY). This pathway is all about making S-adenosyl methionine (SAM) which is the Queen of the methylators. For this pathway to function properly a person has to be getting adequate protein. You specifically need the amino acid methionine which will be changed into S-adenosyl methionine (SAM). The cycle can not even begin before it gets a source of initial methyl groups which comes from active folate. This is the bare bones basic pathway. SAH competes with SAM for for binding to methyltransferase enzymes, which acts as competitive inhibition, and controls the amount of methylation going on in a cell.
Necessary Enzymes And Cofactors
Although the above pathway is correct, it is missing the enzymes necessary for this pathway to function. Methylation is regulated by the availability of enzymes and co-factors necessary to assist methylation as well as the substrates to be methylated.
Methylation is catalyzed by enzymes. These enzymes themselves need helper molecules called cofactors (which are usually vitamins/minerals) for activation of methylation, to complete methylation and to turn methylation off.
Methionine(MET) turns into s-adenosyl methionine(SAM) with the help of the enzyme methionine adenosyl-transferase(MAT). SAM now donates a methyl group outside of this pathway and becomes SAH with the assistance of the enzyme methyltransferase (MT) and then SAH becomes homocysteine with the help of the enzyme SAHH (S-adenosylhomocysteine hydrolase). It turns SAH into homocysteine with adenosine as a byproduct. It is reversible back to SAH. Finally, methionine is regenerated from homocysteine again via the assistance of the enzyme Methionine synthase(MS). Then the cycle starts all over again. The pathway below has the addition of these enzymes listed in purple.
Additionally, cofactors assist in changing homocysteine to methionine. These cofactors are the B vitamins methylcobalamin (B12) and 5-methyl tetrahydrofolate(5-MTHF). MS will not be able to convert homocsteine into methionine without them. These cofactors are listed in green below.
The importance Of Folate
I should mention that 5-methyl tetrahydrofolate(5-MTHF) is what we call "active folate". You will also see it called levomefolic acid (levomefolate), L-methylfolate and (6S)-5-methyltetrahydrofolate. Do not confuse this with folic acid which is also called B9. We are talking about active folate here. It is an activated B vitamin that is the end product of the "Folate Cycle". As you can see the methionine cycle can not function without it, so the folate cycle becomes an important part of the methylation pathway. For the folate cycle to function properly it also requires enzymes and cofactors. To see both a simple and a detailed folate cycle with a simple methionine cycle attached go to this link.
Enzymatic Issues In Many Individuals Do Not Allow Use Of Synthetic Folic Acid
If your folate pathway is fully functioning you will make 5-MTHF. However, if you have any enzymatic issues due to SNPs (genetic variations), or if you are missing certain cofactors in the diet you will have issues. The starting point for this pathway is ingestion of dietary folate. Synthetic folic acid or B9 is also a starting point. However, about 1 in 3 Americans can not process folic acid (synthetic form of folate) and it becomes unmetabolized folic acid. There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intake that overwhelms the liver's metabolic capacity, may be associated with adverse effects.
There is an alternative route for homocysteine to become methionine via the BHMT pathway which is incorporated into this more comprehensive methionine cycle below. Details of this cycle are written out below.
Methionine Cycle In Detail
Enzyme Abbreviations Explained
MAT = methionine adenosyltransferase - needs ATP to turn methionine into SAM the universal methyl donor.
MT = methyltransferases - Turn SAM into SAH (S-Adenosyl Homocysteine) SAH is an inhibitor of all methyltransferase reactions.
SAHH = S-adenosylhomocysteine hyrdrolase - Turns SAH into homocysteine with adenosine byproduct. Is reversible back to SAH.
MS = methionine synthase - b12 dependent enzyme changes homocysteine into methionine
BHMT = betaine homocysteine methyltransferase - zinc dependent using trimethylglycine to change homocysteine into methionine.
A Quick Look At The Methionine Cycle
Lets take a look at the individual main components of the methionine, or methylation cycle above. We have methionine that is turned into S-adenosylmethionine, that is turned into S-adenosylhomocysteine that is turned into homocysteine, and it finally is turned back into methionine again.
Methionine (MET) is a sulfur containing amino acid which enters the body through dietary proteins. It is an essential amino acid. This means we have to ingest it. We can not make it. Methionine is essential for the synthesis of proteins, and many other biomoleules required for survival. Rats fed a diet without methionine develop fatty liver disease which can be corrected by methionine supplements. Methionine has a methyl (CH3) group attached to its sulfur atom. Methionine's methyl group becomes activated by ATP (adenosine triphosphate) with the addition of adenosine to the sulfur of methionine, adjacent to the methyl group to form S−Adenosyl Methionine (SAM also written SAMe) which is the universal methyl group donor.,The methyl group on methionine is used for adding methyl groups to numerous kinds of molecules, but only after methionine has been activated by ATP.
S-adenosylmethionine (SAM) is the universal methyl group donor for a variety of methyltransferases, resulting in the methylation of substrates such as nucleic acids, lipids, and proteins. SAM is generated via the activation of methionine by methionine adenosyltransferase (MAT) and the assistance of ATP When SAM gives up a methyl group it is turned into SAH.
All SAM dependent methyltransferase reactions result in the production of S-adenosylhomocysteine (SAH), which can subsequently be converted to homocysteine by SAH hydrolase or it is changed into adenosine. SAH is a strong inhibitor of most methyltransferases, so it must be removed for the cycle to continue.
homocysteine can continue on in the methionine pathway and be remethylated back to methionine by folate dependent, and independent mechanisms, or in the liver homocysteine can be catabolised via the transsulfuration pathway. Let's look at these three options.
1. Homocysteine In The Transsulfuration Pathway
In liver cells and to some degree the kidney homocysteine can irreversibly enter the transsulfuration pathway (catalyzed by Vitamin B6) to produce the amino acid cysteine. It will then be on an irreversible course in which the cystathionine B-synthase (CBS) enzyme will change it into cystathione. Ultimately it could end up as some other necessary compound such as glutathione. It has been estimated that 60% of homocysteine is metabolized by transsulfuration in the liver, with glucocorticoids increasing that percentage. Cysteine can be incorporated into proteins, can be used in the formation of the anti-oxidant molecule glutathione (GSH), or can be oxidized to form the amino acid taurine. (Selenium deficiency increases transsulfuration of homocysteine, and decreases global DNA methylation)
If homocysteine does not enter the transsulfuration pathway, it can be converted back to methionine by the addition of a methyl group by one of two pathways.
2. Folate Dependent Remethylation
The B12 dependent enzyme methionine synthase (MS) uses a methyl group from 5-methyltetrahydrofolate (5MTHF) and adds it to homocysteine to create methionine.
3. Folate Independent Pathway
For the folate independent pathway(only in the liver and kidney) the enzyme Betaine-homocysteine S-methyltransferase (BHMT) is used to catalyze the remethylation of homocysteine. BHMT is zinc dependent. Glycine betaine or tri methylglycine (TMG) is a methyl group donor derived from choline oxidation. It transfers a methyl group to homocysteine to become methionine. Di-methylglycine (DMG) is a feedback inhibitor here. This pathway appears to be working poorly in people with Chronic Renal Failure where homocysteine is high, DMG is high and zinc is low.
If there is inadequate 5-MTHF, or inadequate B12, homocysteine will accumulate in the cell. Homocysteine accumulation leads to a back up of SAH accumulation which can lead to dysregulation of gene expression, protein function, lipid metabolism, and neurotransmitter metabolism due to inhibition of methyltransferases.
Decreased BHMT activity increases homocysteine levels significantly.
Elevated homocysteine levels are an indicator of a problem with the methionine cycle/folate cycle or related cycles such as CBS. Elevated homocysteine levels are usually easy to correct.
Dietary Supplements, Herbs, Dietary Changes, Lifestyle Changes
Substrates/cofactors that are used for methylation (includes substrates needed for BHMT pathway, folate pathway and methionine pathway): choline, methionine, folate or more active form, vitamin B6 (P-5-P), B12 (methylcobalamin), Riboflavin, zinc, betaine(TMG). Other substrates may be used, but these are the most basic ones used. Other SNP variations such as in COMT, or the CBS cycle can effect methylation, so the larger pictures always needs to be examined to decide what substrates/cofactors are beneficial for each individual.
Methionine Synthesis B Vitamins & B12 Deficiency
Methionine synthesis requires at least 4 vitamins. They are B12, folate, vitamin B6 and riboflavin. The intake of these vitamins is thought to be suboptimal in as much as 40% of the population. B12 and folate are the two most likely to be deficient. B12 should be tested by a methylmalonic acid test. Other tests are not as sensitive. Megaloblastic anemia is seen in both folate deficiency as well as B12 deficiency They are the two most common causes of megaloblastic anemia. It is important to know that folic acid (vitamin B9), especially when taken in high doses, can mask the symptoms of a vitamin B12 deficiency. The danger is that without symptoms, someone with a vitamin B12 deficiency may not know it, and could run the risk of developing nerve damage. B12 deficiency can include symptoms such as fatigue, shortness of breath, nervousness, numbness, tingling sensation in the fingers and toes, loss of balance, pale skin, diarrhea, weakness, confusion, memory loss and moodiness. Vitamin B-12 deficiency is often caused by the lack of a protein in the stomach called “intrinsic factor.” Without intrinsic factor, vitamin B-12 can’t be absorbed, regardless of how much you eat.
B6 foods: rice bran, sunflower seeds, Pistachio nuts, tuna, turkey, chicken, pork, tuna, prunes, lean beef, bananas, avocados, banana, Spinach, shitake mushrooms, molasses, summer squash, potato, sweet potato, leeks, pheasant, octopus, kale, collards, oatmeal, beans
B12 foods: clams, liver, fish such as salmon and tuna, lamb, crustaceans(shrimp, crayfish, lobster), beef, dairy, eggs, halibut, chicken Vegetarian sources: brewers yeast, nori,wakami, kombu,chlorella, spirulina.
Riboflavin foods: beef kidney, beef liver,chicken liver, beef heart, oily fish, yogurt, eggs, pork, mushrooms, sesame seeds, broccoli, almonds, sea food, brewers yeast, cheese, wild rice, spinach
Zinc foods: oysters, beef, wheat germ, turkey, cheese, potato, oats, mustard greens, pumpkin seeds, tuna, rice, beans,
Choline foods: egg yolk, whole egg, beef, wheat germ, fish, pork, fish, turkey, shitake, broccoli, shrimp, milk, peanut butter. Choline is made from phosphatidylcholine or lecithin. You can take this to make choline. A good source of lecithin is sunflower seeds.
Betaine foods: quinoa, lambs quarters, beets, broccoli, shellfish, rye and other grains, fish, spinach
Methionine foods: tuna, salmon, cheese,shrimp, pork,eggs, milk, chocolate, cashews, walnuts, turkey, sausage, almonds, duck, chicken, filberts, sesame, peanuts, potato, sweet potato, avocado
Starting methylation support can make a person feel great or can cause them some severe reactions. Therefore a person should not support methylation unless they need it, and they have examined their biotransformational/detox cycles as a whole. A knowledgeable practitioner is useful and usually necessary at this juncture. Before supporting methylation, make sure the persons diet is good, they are in a healthy environment and their digestive system is in good working order. This is the ground work that is necessary to begin. If a person is in a moldy environment, or they are working with toxic chemicals you may not be able to address their methylation issues properly. Additionally, if they have a heavy metal burden or have a viral or bacterial burden this will affect their biotransformational cycles too. Starting methylation under this kind of ongoing stress will also encourage sudden, and significant detoxification which may make the person feel really sick.
When it is needed, it is best to start slowly with methylation support. Rather than simply throwing all the substrates at a person with inadequate methylation, it is best to start with one, or two at a time that are indicated. As time allows add other necessary substrates slowly, and always in small amounts at first. What is indicated will depend on a complete analysis of the person including an examination of their biotransformational pathways.
Nutrients/Supplements Used in Methylation Support Protocols
Which of the nutrients/supplements are used and when they are used, depends on the SNPs each person has, as well as their clinical picture. You have to take into account their physical, mental, emotional, and spiritual profile before using these or any other methods. These are just a list of supplements that may be used by a practitioner when needed. I definitely do not suggest that a lay person simply start taking all these items listed below as they may cause themselves discomfort. Likewise it would not be prudent for a practitioner to start someone on all these supplements either. Each person will need an individualized protocol depending on their "big picture."
Riboflavin (B2): The activated forms of B2, flavin mononucleotide (FMN) and Flavin Adenine Dinucleotide (FAD) are required for important reactions in all species. FAD is needed for MTHFR to make 5-MTHF You need thyroxin (T4) to convert the b2 into the active FAD. Riboflavin can be synthesized in bacteria, parasites, fungi, plants and some animals but mammals have lost the ability to make it. Instead, we have to obtain riboflavin from our food and that's why it's a necessary vitamin in humans. Riboflavin deficiency is rare because we can usually get enough from the bacteria that inhabit our intestines. It is seen in chronic alcoholics who often show deficiencies in many other vitamins as well.
TMG (trimethyl glycine)– If there is an issue in the BHMT pathway
Choline can be helpful or lecithin (sunflower seeds) to make choline if there is a PEMT issue. However taking TMG bypasses the need for choline in this pathway.
Sublingual methylcobalamin and /or (hydroxycobalamin if the person is overmethylated due to other transformational pathway variants and needs B12 - yes this may not make sense to you and we won't go into it here.) hydroxyl will work as it has to be methylated and this actually decreases the methyl groups when there are too many. The hydroxyl form would not be good for a low methylator which is actually what we are addressing here.
Vitamin E 400 IU, especially if the person also has a CBS issue: Other CBS/SUOX support to consider would be molybdenum, boron, hydroxy B12, yucca with protein, diet change to decrease S. See CBS/SUOX Page when I get around to writing it. Also see short definition on bottom of this page.
D3 - need to follow lab levels, I want in 50 range - Vit D council recommends this. Take D3 with K2.
Vit C – critical as cofactor, also helps recycle glutathione
Krill Oil/Fish Oil – Thought to cross blood brain barrier better than fish oil. So considered better for brain, or can use fish oil (good for inflammation). The way most are processed, unsure if they are good for folks really. Eat oily fish (be careful of mercury), there is also fermented fish oil.
Milk thistle – 1 Tablespoon freshly ground seed BID is used for liver support and to make glutathione
Tumeric/Curcumin - Use good curcumin product such as Meriva-500 (2-3 caps BID) from Thorne or take 2-3 Tablespoons of turmeric twice per day. I have found the Meriva to work well, although anytime you take curcumin it helps to take some whole Turmeric also with it. Meriva by Thorne is nice if you don't like taking large doses of tumeric. Some folks get tired of the taste and others are fine with it.
Green tea - 1-2 cups per day. Drink before 3PM. I prefer this but also consider Green tea polyphenols - Take 500 mg BID or two cups of strong green tea per day. epigallo-catechine gallate (Green tea catechins):(EGCG), a major (and the most active) component of green tea extracts inhibits TGF-beta.
Magnesium glycinate or citrate is helpful with spasms often also. Spasms can be from other things, but low magnesium is common. If you take too much you will have diarrhea and it can irritate your gut.
Selenium helps recycle glutathione
Zinc – critical cofactor in many methylation processes
CoQ10, L-carintine. creatine (sp for mitochondrial support for folks with muscle pain)
These nutrients are not necessary if giving methylfolate, methylcobalamin, and magnesium don’t need to give these nutrients usually then.
Glutathione – start small, can cause feedback inhibition in CBS enzyme – instead make your own glutathione with milk thistle, selenium, NAC, zinc, or any other nutrient you might be short on to make and recycle glutathione. See Glutathione link.
Probiotics - Necessary to absorb toxins, IGA and reduce acetylaldehyde. If your gut is working well and you have good gut bugs, there will be less need for your body to use methylation on toxins.
Multi vitamin with complete minerals: May be helpful, rather than taking many single products. Some products are made specifically for methylation support. These can be a great resource.
Electrolytes are lost via urine from adrenal fatigue and frequent urination – good one by Elyte, I think Ben Lynch has a good one.
Adaptogen herbs - The adaptogen herbs support the mitochondria and they are involved in DNA methylation. Consider if someone needs adaptogen herbs. If they are showing signs of "adrenal fatigue", they may be helpful.
Potassium: Potassium is used as a neutralizer of side effects - Individuals can hurt themselves if they take too much. Too little and too much are both an issue. I usually suggest individuals do not take potassium unless working with a practitioner. High potassium foods are a safer way to go than potassium supplements, although anyone with kidney issues, should be careful how much potassium they are getting in food.
Methyl Guard Plus: Thorne has a nice product called Methyl-Guard Plus used to enhance methylation. It contains riboflavin, P-5-P, l-5MTHF, trimethylglycine, and methylcobalamin (B12).
Specific Nutrients That Use Methylation To Create Them
L-carnitine is the compound that transports long-chain fatty acids into the mitochondria so they can be broken down for energy. In fact, it is one of the few natural materials known to allow fats to cross the mitochondrial membrane, so it is crucial to fat metabolism. This is important because mitochondria fatty acid oxidation is the main energy source for heart and skeletal muscle. The synthesis of carnitine in the body begins with the methylation of the amino acid L-lysine by SAM.
Coenzyme Q10 is an enzyme essential to the production of ATP—it’s involved in 95% of the energy-producing reactions in your body through its role in electron transport. CoQ10 delivers electrons to precisely the right places during the formation of ATP. CoQ10 is also a very powerful antioxidant, which helps to protect the mitochondrial membrane and cell walls from attack by free radicals. And just as with carnitine, the synthesis of CoQ10 by your body depends on the methylation pathway.
Low muscle tone and extreme muscle weakness, which we often see in children with autism and adults with chronic fatigue, appears to be due to decreased mitochondrial energy and, as we will see below, to myelination problems resulting from reduced methylation cycle capacity.
Genetic Overview Of Enzymes And Pathways Important For Methylation Or Methionine Cycle
This is used in the Trans-sulfuration pathway. It converts homocysteine into cystathionine. If upregulated, it will deplete methyl groups. It is a step in the process of increasing taurine, sulfate and glutathione, a major antioxidant. Certain types of mutations in the CBS genes may produce more sulfur end products from the methylation cycle. It is possible that particular, individuals who have the CBS (+/+, or +/-) the homozygous, or heterozygous variants may want to limit intake of sulfur-containing foods (like crucifers, garlic, and supplements, such as MSM as well as medications like DMPS.) Both the CBS homozygous and heterozygous mutations also have a higher risk for ammonia detoxification issues.
COMT processes catabolism of dopamine, norepinephrine and estrogens. A primary function of the COMT gene is to help to break down dopamine. Dopamine is a neurotransmitter that is recognized for its role in attention, as well as reward-seeking behavior. It enhances pleasurable feelings that aid in reinforcing positive behaviors. The balance between norepinephrine levels and dopamine levels has been implicated in ADD/ ADHD; in addition, dopamine levels are important in ailments such as Parkinson’s disease. COMT is also involved in the proper processing of estrogen in the body. COMT val/val (–/–) individuals break down dopamine effectively, and as such will be depleting methyl groups from the cycle and can tolerate more methyl group supplementation. With COMT met/met (+/+), the homozygous mutation, the enzyme works sluggishly, essentially slowing down methylation of brain chemicals. With this profile, people may need to limit, or avoid methyl donors, as excess methyl donors can lead to hyperactivity, irritability, a feeling of being out of control and erratic behavior.
MTHFR (Methylenetetrahydrofolate reductase)
The MTHFR gene products are at a critical point in the methylation cycle. One function helps to convert homocysteine into methionine, serving to keep homocysteine levels in a normal healthy range. Several mutations in the MTHFR gene have been well characterized as leading to increased homocysteine levels, which increases the risk of heart disease, Alzheimer’s, and cancer. Other genetic variations in MTHFR may play a role in the level of the neurotransmitters serotonin, and dopamine, as well as the conversion of BH2 to BH4.
MTR and MTRR (Methionine Synthase/ Methionine Synthase Reductase)
These two gene products work together to regenerate, and utilize B12 for the critical “long way” around the methylation pathway, helping to convert homocysteine to methionine. Mutations in MTR can increase the activity of this gene product so that it leads to methyl group depletion and greater need for B12, as the enzyme is using up B12 at a faster rate. The MTRR helps to recycle B12 for use by the MTR. Mutations that effect its activity would also suggest a greater need for B12.
NOS (Nitric Oxide Synthase)
The NOS enzyme plays a role in ammonia detoxification as part of the urea cycle. Individuals who are NOS (+ /+) have reduced activity of this enzyme. NOS mutations can have additive effects with CBS up regulations due to the increased ammonia that is generated by the CBS up regulations. Mutations in NOS may also play a role in dealing with proper processing of oxidized species. This may be important with respect to oxidized species generated by the mitochondria and impact energy, as well as play a role in the aging process and our risk for cancer.
GAD (Glutamate Decarboxylase)
Transforms glutamate to GABA
HNMT (Histamine N-methyltransferase)
Processes histamine (secondary enzyme for histamine; primary is DAO)
QDPR (Quinoid Dihydropteridine Reductase)
SUOX (Sulfite Oxidase)
Processes sulfites/sulfur and this mutation is made worse from CBS upregulation. Helps to detoxify sulfites in the body. It helps change sulfites into sulfates. Sulfates are useful to our body. Sulfites are generated as a natural byproduct of the methylation cycle as well as ingested from foods and preservatives we eat. Sulfites can also come from the diet as they are used to prevent rust, and scale in boiler water that is used to steam food, and even in the production of cellophane for food packaging. Because many reactions have been reported, the FDA requires the presence of sulfites in processed foods to be declared on the label. Difficulty in breathing is the most common symptom reported by sulfite-sensitive people. Sulfites give off the gas sulfur dioxide, which can cause irritation in the lungs, and cause a severe asthma attack for those who suffer from asthma. A person with SUOX (+/-) should be extremely careful with sulfur foods and supplements. Molybdenum is needed for this enzyme to work.
ACE (Angiotensin Converting Enzyme
Technically, the changes that affect the activity of this gene are not a SNP but a deletion (that means that a base is eliminated rather than substituted as occurs with a SNP) that can lead to elevated blood pressure. In animal studies, imbalances in this pathway were also correlated with increased anxiety and decreases in learning and memory. Increased ACE activity can also throw off the essential mineral balance in your system due to decreased excretion of sodium in the urine and increased excretion of potassium in the urine, provided the kidneys are functioning properly. Decreased potassium can also lead to fatigue and decreased energy production. This reaction is also tied to the stress response, in that situations of chronic stress can result in additional sodium retention and increased potassium excretion.
BHMT (Betaine Homocysteine Methyltransferase)
The product of this gene is central to the “shortcut” through the methylation cycle for converting homocysteine to methionine. The activity of this gene byproduct can be effected by stress, and may play a role in ADD/ADHD by effecting norepinephrine levels.
SHMT (Serine Hydroxymethyltransferase)
This gene product helps to shift the emphasis of the methylation cycle toward the building blocks needed for new DNA synthesis, and away from the processing of homocysteine to methionine. While DNA building blocks are important, mutations that effect the ability to regulate this gene product, and interfere with the delicate balance of the methylation cycle may cause accumulations in homocysteine as well as imbalances in other intermediates in the body.
AHCY 1,2,19 (S-Adenosylhomocysteine Hydrolase)
These gene byproducts promote activity through the portion of the pathway that goes from methionine to homocysteine, effecting levels of homocysteine and ammonia. Therefore, the AHCY mutations will limit those activities, and may partially mitigate the effects of CBS upregulations, such that taurine levels remain moderate rather than elevated.
ACAT 102 (Acetyl Coenzyme A Acetyltransferase)
This gene byproduct contributes to lipid balance, helping to prevent the accumulation of excess cholesterol. ACAT is also involved in energy generation, through supporting the conversion of protein, fats and carbohydrates (from food) into energy. As a result ACAT mutations impact lipid balance, cholesterol levels, and energy levels, and may also deplete B12, which is needed for the long route around the methylation cycle.
PEMT (Phosphatidylethanolamine N-Methyltransferase)
This gene interfaces between the methylation cycle and estrogen. People report that a modified form of the program used for autism also appears to benefit chronic fatigue syndrome (CFS), a condition that effects more women than men. In addition, in the methylation cycle, PEMT helps to convert phosphatidylethanolamine to phosphatidylcholine. Moreover, PEMT requires methyl donors for its activities and may therefore both impact (and be impacted by) methylation cycle imbalances.
Testing Homocysteine Levels
Home tests are not accurate and should not be used. Consumption of high methionine foods can give false results on the test. The patient needs to fast for 12 hours prior to having blood drawn. The sample must be put on ice immediately, or the red blood cells need to be spun out right away.
Spectracell: Has good rates for tesing A1298C and C677T
(Before working on MTHFR, MTRR and or MTR mutation protocol, address the CBS and SUOX mutations.)
Interesting Tid Bit About Coffee And Methylation
Coffee has numerous methyl groups and this is why it causes an increased ability to focus your attention.
A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimer's disease (AD). The beneficial effects of EHT appears to be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. (Basurto-Islas, 2014)
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