Methylation is an important chemical process that happens in our bodies and is part of hundreds of essential reactions. It is the addition of a chemical compound (a methyl group – CH3) that changes the nature of compounds in the body for various reasons.  Wikipedia tells us that “In biological systems, methylation is catalyzed by enzymes; such methylation can be involved in modification of heavy metals, regulation of gene expression, regulation of protein function, and RNA processing.”

So what are the processes that involve methylation?

Genes, Transcription & Epigenetics. Methylation plays a vital role in DNA transcription and DNA methylation is both essential for normal development (formation of enzymes and proteins) and to alter the expression of genes ( DNA methylation results from the transfer of a methyl group  in the C5 site of cytosine, creating the 5-methyl-cytosine (5mC), by DNA methyltransferase (DNMT) enzymes).

Epigenetic means “above” genetics, or the part of our gene expression that is modified through experience and this requires methylation.

Methylation is also involved in the preservation of telomeres (“end part”), the protective ‘caps’ at the end of DNA and chromosomes.  The shortening of telomeres is associated with ageing.

Neurotransmitter synthesis.  Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), is involved in the re-methylation of the amino acid metabolite homocysteine (a toxic waste by-product of protein and amino acid metabolism), creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters (so basically taking a toxin and turning into something useful! Too much homocysteine in the system can cause many health issues). Some people have some difficulty resynthesizing methionine from homocysteine, increasing the chance of cardiovascular disease, depression, fatigue and exhaustion.

Dopamine, an important neurotransmitter is synthesised from L-DOPA and in turn epinephrine and then norepinephrine are synthesised from dopamine (These are all excitatory transmitters). Similarly we rely on the methylation process to form the inhibitory transmitters including GABA and serotonin.

Cofactors (helper molecules) are also involved in this rather complicated synthesis process – for example GABA is synthesized from glutamate using the enzyme L-glutamic acid decarboxylase (GAD) and pyridoxal phosphate as a cofactor (which is the active form of vitamin B6). Methylation is also involved in producing myelin for the brain and nervous system.

Detoxification, Hormones and Inflammation.  Methylation is also a process the body uses to convert toxins into water-soluble compounds so they can more easily eliminated from the body as well as being involved in such processes as the synthesis of glutathione that is also involved in detoxification and anti-oxidation.

Closely related to detoxification is the balance of hormones, and so methylation in a vital part of the chain that results in the proper balance of hormones including oestrogen’s (which may help limit the chances of cancer related to hormone imbalance).

Inflammation is one of the biggest factors leading to ill health. I remember one researcher saying that if you didn’t get hit by a truck then inflammation was going to kill you!  The reasons for inflammation are many, including allergic responses to many things like food and environmental toxins (or just about anything), and a system that is out of balance with neurotransmitters, hormones, enzyme production, toxin removal, etc.

Energy Production.  The mitochondria are the power plants within our cells and mitochondria DNA methylation is a critical process for adaptive energy production in cells. Mitochondria not only provide cellular energy, but are are involved in other tasks, such as signalling, cellular differentiation, and cell death, as well as maintaining control of the cell cycle and cell growth. So you can imagine just how important the proper functioning of mitochondria is to your overall wellbeing. Within the mitochondria is coenzyme Q10 – a component of the electron transport chain and involved in aerobic cellular respiration, generating energy in the form of ATP (95% of the human body’s energy is generated this way).

METHYLATION BIOCHEMISTRY
methylation-cycle

Some of the main players in the methylation pathway are Tetrahydrofolate (THF), Folinic acid (5-formyl THF), and Trimethylglycine (TMG) in the folate metabolism pathway that form methyl groups for the methionine metabolism pathway (that includes: homocysteine, methionine, S-adenosylmethionine (SAMe) and S-adenosylhomocysteine (SAH)). These molecules cascade from one to another by means of enzymes. The important co-factors (helper molecules) that allow this to happen are the B vitamins such as folic acid, vitamin B12 and vitamin B6. For example S-adenosyl methionine converts to S-adenosyl homocysteine, by giving up a methyl group and this can be used to stick on to other molecules. For the methylation cycle to work the B vitamins need to be in an activated form (methylcobalamin, folinic acid and pyridoxyl-5-phosphate). These metabolic pathways are very complex and involve many more elements than I’ve described here, but for the purpose of gaining a rudimentary understanding of methylation, these will do.

Over-methylation

 Over-methylation (as you would guess is too many methyl groups produced in the system), can result in excessive levels of the neurotransmitters that can produce symptoms such as  reduced motivation, reduced libido, weight gain,  food sensitivities, irritability, anxiety, confusion….the list can be long and varied depending on what source you are looking at – and this is a complex and individual thing – According to Carl Pfeiffer (a physician and biochemist who researched schizophrenia, allergies and other diseases), the condition is characterized by elevated levels of serotonin, dopamine and norepinephrine, low whole blood histamin and low absolute basophils. And people with with this condition tend to have classic signs, including canker sores, difficult orgasm with sex, no headaches or allergies, heavy growth of body hair, ideas of grandeur, undue suspicion of people, racing thoughts, the feeling that someone controls one’s mind, seeing or hearing things abnormally, ringing in the ears, high anxiety and food sensitivities. Also a decrease in blood histamine (from high copper levels) is also linked with psychosis.

Prof. Pfeiffer has given us a rather dramatic list of symptoms but there is no ‘typical’ profile as the methylation process may affect different elements in differing amounts (in other words, we are all individuals with unique characteristics and ways of responding). Some researchers say that over methylation is rather rare.

Under-methylation

Not producing enough of the methyl groups can cause symptoms such as fatigue, depression, obsessive, compulsive and addictive type personalities, good tolerance of cold, poor tolerance of heat, unexplained nausea, poor pain tolerance, excess/abundant saliva in mouth, hyperactivity, frequent colds/flu, phobias, highly motivated and hard-driving personality, good creativity/imagination, high libido, joint pain/swelling/stiffness, excess perspiration and warm skin, obsessive-compulsive tendencies, “oppositional-defiant disorder,” seasonal depression, and seasonal allergies. When there is psychosis from under methylating, the dominant symptom is usually delusional thinking rather than hallucinations, according to Dr. Willian Walsh, a former senior scientist at the Pfeiffer Treatment Center. They may appear outwardly calm, but suffer from extreme internal anxiety.

People who are under methylating may have a tendency to be very depressed in calcium, magnesium, methionine, and vitamin B-6 with excessive levels of folic acid.

SOURCES OF METHYL GROUPS

A healthy body will produce many methyl groups and are also found in natural foods – eat plenty of dark green cooked vegetables, as fewer are absorbed from raw foods. In fact any foods rich in natural folate, or Vitamin B9, including strawberries, citrus fruits and leafy green vegetables, and Vitamin B12 (fish, meat, milk, and eggs) will yield the methyl groups you need.  Also choline oxidizes to form a source of methyl called Betaine, which is found in its highest concentration in beef liver (and in toasted wheat germ, eggs cod, beef, brussel sprouts, broccoli, shrimp and salmon).

Supplements to help produce methyl groups include TMG or trimethylglycine, (also called betaine). You should take such supplements under the instruction of a professional who knows what they are doing and knows what is going on in your body – too much of a good thing can be very bad for you!

Sugars appear to be harmful for proper methylation (as well as increasing inflammation) and many orthomolecular specialists will advise against eating too much simple carbohydrates or sugars, including fruits and fruit juices. Some say that too much methionine (an essential amino acid, of which high levels can be found in eggs, sesame seeds, Brazil nuts, fish, meats and some other plant seeds) in some diets may negatively affect methylation. Fighting infection or dealing with inflammation in the body will use up more methyl groups as well as detoxification (because the body is using methyl groups to convert the toxins to something more easily eliminated)

SO WHAT?

So what does this have to do with your mental health? Well, just about everything. Metabolic pathways, of which methylation is an important factor, can be dysfunctional, leaving us with the wrong balance of neurotransmitters, unable to process toxins efficiently, knocking our hormones off balance – all affecting our mental processes. If the wetware (our brain) isn’t functioning properly then our state of ‘mind’ is going to struggle – it will try it’s best to adapt and cope, but we will become dysregulated and psychotherapy, counselling, and well meaning relatives will have limited efficacy for your wellbeing.


Good to Know:

Folate Metabolism Pathway

The folate metabolism pathway forms methyl groups that are used in the methionine metabolism pathway, and acts as a regulator of that pathway. Folates naturally occur in vitamins found in many foods (Folic Acid is a synthetic for of folate).

Methyl groups come from either trimethylglycine (TMG) that happens in the kidney and liver, or 5-methyltetrahydrofolate (5MTHF) that happens in most cells in the body. 5MTHF is the most abundant folate form in plasma and is therefore the most prominent form for the methylation process. Enzymes (MTR & MTHFR) convert 5MTHF into tetrahydrofolate (THF) and in the process donate methyl groups to homocysteine to form methionine (see pathway below). Folinic acid (5-formyl THF) is an active and reduced form of folate that also plays an important part in providing the body with other active form of folate.

Methionine Metabolism Pathway

S-Adenosyl Methionine (SAMe) is the most active methyl group donor in the body and is formed in the Methionine Metabolism Pathway (Transmethylation). SAMe is formed through amino acid methionine and ATP reactions. As SAMe releases methyl groups to the methylation process, it is converted to S-Adenosyl Homocysteine (SAH), which in turn is converted to homocysteine. Homocysteine is re-methlyated to form methionine. SAMe functions to promote the synthesis of DNA/RNA, Glutathoine, CoQ10, creatine, carnitine, inhibition of histamine and the conversion of serotonin to melatonin (among other things).

Elevated SAMe levels can be due to excessive supplementation and elevated SAH (an inhibitor of the methylation process) may suggest inadequate homocysteine metabolism to methionine.

 

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