I'm sure that you've come across the term "methylation" - maybe even in your own DNA reports or when you've had blood tests, and you've had your homocysteine level evaluated. Methylation is complex. And important. But unless we completely understand its role in our bodies, then we may not make the necessary health choices to ensure that we are methylating right.
In Functional Medicine, methylation is one of the key biological systems that is looked at to help you prevent associated chronic diseases. Determining your genotype for the key genes involved in methylation together with your current methylation biomarkers, diet, supplementation, environment, and lifestyle choices; you'll be in a much better position to prevent problems such as hormonal imbalances, autoimmune disorders like arthritis, cardiovascular disease, infertility, mood disorders, digestive problems linked to poor bile production, memory problems, chronic fatigue, mitochondrial function, and chronic inflammatory disorders.
Reading this, you should be thinking that methylation plays a role in almost all aspects of your body. You're right, methylation is everywhere or what we call "global" meaning that it happens in every single cell in your body. Billions of times, everyday.
The methylation cycle versus DNA methylation
It's important when reading up about methylation or when reviewing your DNA report, to be aware that there is a difference between DNA methylation and methylation.
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. It is an epigenetic mechanism that can change the activity of a DNA segment without altering its sequence but rather acting as a switch to turn on and off gene expression.
Methylation is the addition of a methyl group to a substrate/surface or enzyme. A methyl group is a small molecule made of one carbon and three hydrogen atoms. Methyl groups are added or removed from proteins or nucleic acids and may change the way these molecules act in your body. The methylation pathway is tightly regulated by positive and negative feedback mechanisms to either activate or inhibit function.
| DNA Methylation | Methylation Pathway |
| This refers to the methylation, activated sights on DNA. These methylation tags can be measure using epigenetic tests. | Methylation is the process by which a methyl group is added to a substrate/surface (e.g your liver) or an enzyme deep in your biochemistry. |
The tricycle of methylation
Imagine a tricycle or three wheels turning together - that's what your methylation pathway looks like. The methylation pathway is made of 3 important biochemical cycles, namely the methionine cycle, folate cycle, and homocysteine transsulfuration cycle and each of these requires certain important co-factors called methyl donors nutrients from your diet and supplementation choices to ensure that it is functioning optimally.
Methyl groups and their donors
Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl groups can be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism.
Knowing this helps you to understand the importance of your diet and supplement choices. When we know that our food acts as a methyl donor, we really start to see that "we are what we eat" and that the nutrients we consume are actually information to our DNA and biochemistry.
Am I over-methylating or under-methylating?
It is also helpful to be in-tune with your body and be aware of the common signs of either over- or-under methylation.
Is there a "methylation genotype"?
To take the guesswork out of methylation it is extremely helpful to determine your "genotype" so that you can start to pinpoint whether you've high impact genetic variations in the key genes involved in methylation.
| Gene | Risk Allele | Impact | Biomarker | Support |
| MTHFR | T-allele |
Reduces enzyme activity to remethylate homocysteine back to methionine. Predisposes you to lower blood folate (5-MTHF) & higher homocysteine. |
Homocysteine levels | 400- 800ug folate daily |
| MTR | A-allele and G-allele | Associated with reduced activity and therefore potentially the buildup of homocysteine | Homocysteine | B12 |
| MTRR | G-allele | An accumulation of homocysteine, which is in turn associated with a variety of disorders including cancers, heart disease, stroke, raised blood pressure and potential issues with birth defects. | Homocysteine blood levels |
B12 Methionine |
| BHMT-02 | A-allele | Associated with increased homocysteine levels. | Betaine levels | Betaine supplementation |
| PEMT | A-allele | Decreased phosphatidylcholine, slower bile flow, muscle function, liver, and brain function. | Choline | Choline, green tea, and SAM-e |
| SUOX | T-allele | Decrease ATP, deplete glutathione, sensitivity can lead to asthma and low blood sugar. | Sulfite oxidase | B12 |
| CBS | T-allele | Associated with an accumulation of ammonia. |
Homocysteine Taurine |
B6, iron, choline & folate |
| MAT1A | A-allele | Results in a loss of MAT1A function leading to the development of excess of methionine in the blood, which is also associated with a reduction in the amount of SAM available to act as a methyl donor. | SAM blood levels |
Magnesium Potassium SAM-e |
| MAO-A | T-allele | May be predisposed to an increased risk of major depressive disorder and bipolar disorder. | The metabolites for dopamine, serotonin, and noradrenaline | B2 |
| COMT | A-allele | Displays reduced methylation activity and high homocysteine levels | Homocysteine | Magnesium |
| AHCY | A-allele and T-allele | Results in the reduction in AHCY activity, leading to a build-up of SAH inhibiting the production of SAM-e. | SAH | B3, B12, betaine, folate, choline |
| eNOS | T-allele | Associated with atherosclerosis, essential hypertension, end-stage renal disease, and preeclampsia. | Nitric Oxide |
Exercise Omega 3 Antioxidant |
| VDR | A-allele | Associated with mood, osteoporosis, certain cancers, and diabetes. | D3 levels | D3 |
| SHMT1 | T-allele | Increased cardiovascular risk |
Serine Glycine |
Glycine Soybeans, nuts, eggs, lentils, shellfish, and meat |
| GNMT | T-allele |
Associated with higher homocysteine levels Works to control SAM excess High levels have been linked to prostate cancer |
Sarcosine Glycine |
Folate, SAM-e, D3 |
| CTH | T-allele | Associated with an accumulation of homocysteine. |
Glutathione Homocysteine Cysteine |
Vitamin B6 |
| MTHFD1 | A-allele | Reduces the metabolic activity of MTHFD1 within murine cells by up to 34%. Supplementing with choline before and during pregnancy, and after menopause | Folate |
Nucleotides B12 |
| DHFR | Deletion | Poor conversion of folic acid to tetrahydrofolate | Folate |
Bifidobacterium 5,10 MTHF B12 B9 |
The biochemistry of methylation
Determining your genotype for methylation is a great place to start. However, measuring the key methylation biomarkers is very important as it helps you to determine critical ratios between:
- SAM/SAH
- Un-methylated metabolites/Methylated metabolites
- Transsulfuration/Methylation
| Biomarkers | Pathway | What is it? | Associated Gene | If too high | If too low |
| SAM | Methionine cycle |
It is found in every cell and serves as a sole methyl donor for more than 100 reactions. It also helps to activate the transsulfuration cycle, resulting in glutathione & energy production. |
MAT1A |
Supplement with SAM-e Try to reduce daily calories and check BMI High levels of SAM favours nucleotide synthesis |
Increase protein intake Methionine Magnesium Potassium Supplement with nucleotides |
| Methionine | Methionine Cycle |
An essential amino acid that plays a critical role in methylation.
|
MAT1A |
Lack of cofactors ATP, magnesium and potassium Too much alcohol or oxidative stress Vitamin B6 deficiency |
Poor protein diet Increase methionine intake |
| Choline | Methionine Cycle | An essential nutrient for cell membrane health. A precursor for the neurotransmitter phosphatidylcholine |
Indicates upregulation of betaine/choline backup pathway High choline supplementation/diet |
Not enough choline in the diet | |
| Betaine |
Methionine Cycle |
An amino acid that acts as a major methyl donor to regulate cell volume. | BHMT-02 | Over supplementation |
Increase choline supplementation |
| Serine | Methionine handing over to Folate Cycle |
A nonessential amino acid in protein biosynthesis. Play a role in glutathione production. Abnormalities in the glycine-serine pathway have been linked to cancer |
SHMT1 | The diet is high in eggs, meat, shellfish, nuts, soybean, lentils |
The diet is low in glycine/serine-rich foods Low energy Poor mitochondria function |
| SAH | Methionine cycle |
The metabolic precursor of homocysteine. This is the end-product of the methylation reactions in your body |
ACHY |
High SAH levels are linked to many chronic diseases such as cardiovascular disease, renal disease, & Alzheimer's Genetic variation in ACHY Low levels of folate, B12, B3, betaine & choline
|
Lack of methyl donor SAM |
| Homocysteine | Methionine handing over to Transsulfuration cycle |
An amino acid that is a major branch the methylation pathway It can be metabolised via two pathways - degraded irreversibly through the transsulfuration pathway or re-methylated to methionine |
MTR MTRR BHMT AHCY |
Indicates B6 or iron deficiency which are important cofactors for CBS Enzymatic deficiency in MTR, MTRR, BHMT Low choline intake Too much alcohol and/or tobacco |
Lack of B3 May indicate high levels of oxidative or inflammation |
| DMG | Methionine cycle | An amino acid derivative produced when betaine donates a methyl group to homocysteine for re-methylation to methionine | BHMT-02 |
Indicates a need for folate, B12, and zinc Indicates a genetic variation in BHMT-02 |
Insufficient betaine/choline in the diet
|
| Sarcosine | Methionine cycle | An amino acid that is made when SAM is joined with glycine by the GNMT enzyme | GNMT |
Could indicate over-methylation Taking too high doses of betaine, DMG, SAM-e |
Betaine, SAM-e and folate |
| Glycine | Methionine cycle |
A nonessential amino acid that is 1 of 2 amino acids that make up glutathione A major component of collagen & elastin Has antioxidant, anti-inflammatory, immunomodulatory and cytoprotective roles |
High dietary intake Genetic variations in GNMT Genetic variations in SHMT1 Low B6 and/or iron |
Low dietary intake Indicates over-methylation and excessive methyl supplementation |
|
| Taurine | Transsulfuration cycle |
An amino acid that acts as an antioxidant and neurotransmitter Plays a role in bile production in the liver |
CBS | Good glutathione levels |
High oxidative stress Need glutathione CBS genetic variation |
| Cystathionine | Transsulfuration cycle |
Acts as a transsulfuration pathway mediator Evaluation of this biomarker may indicate a "back-up" of the transsulfuration pathway |
Indicates genetic variation in CBS Evaluated SAM Over supplementation of betaine High oxidative stress & inflammation Needs B6 for CTH enzyme |
B6 for CBS enzyme | |
| Cysteine | Transsulfuration cycle |
Is a nonessential sulfur-containing amino acid Is obtained from the diet and made in the body from cystathionine Plays a role in glutathione and taurine production |
Indicates a CBS genetic impact indicates the presence of high oxidative stress & inflammation Add-in zinc |
Indicates a need for B6 for both CTH & CBS enzymatic function | |
| Glutathione | Transsulfuration cycle |
A tripeptide made up of cysteine, glycine & glutamic acid It is the most potent intracellular antioxidant in your body Involved in phase 2 liver detox by conjugating toxins making them water-soluble to be excreted |
CTH |
Indicates a diet high in amino acid precursors cysteine, glycine & glutamine Shows glutathione supplementation |
Possible poor phase 2 detox Consider glutathione supplementation. Liposomal glutathione is considered to be the best way to increase glutathione levels Consider other genotypes for GSTM1, GSTP1, GSTT1, and GPX1 consider NAC levels too |
| Folate, Folic Acid & Folinic Acid | Folate Cycle |
Known as B9 Is a water-soluble vitamin also produced by GUT bacteria called Bifidobacterium
|
MTR MTRR SHMT1 MTHFD1 |
May indicate over-supplementation Consider SAM levels |
Indicates a need for B12
|
You can find out what your unique ratios are for these methylation biomarkers by ordering the Methylation Profile online
Which micronutrients support methylation?
Adding in the correct micronutrients to support your unique methylation genotype and your current methylation biomarkers is the best way to achieve balanced and healthy methylation.
As you can see, it is definitely not a "one pill solution"! Knowing which micronutrients and amino acids to add in and avoid for balanced methylation is important for optimising your methylation pathway.
| Nutrient cofactor | Methylator type | Supplementation |
| Betaine | Lowers high homocysteine levels | |
| Choline | Supports PEMT & BHMT genetic variations that reduce the bioavailability of
phosphatidylcholine Low levels of choline in the blood |
|
| B3 |
A high impact in genetic variation AHCY High blood levels of SAH |
Daily Vita Life |
| B6 |
A high impact on CBS gene Low cysteine blood levels |
Cortico B5 B6 |
| B9 | Low folate or genetic variation in DHFR, MTHFR, MTR or MTRR | Liposomal B-complex |
| B12 |
Genetic variation in DHFR Low blood folate levels |
Oral Spray B12 |
| Magnesium |
High impact genetic variation in COMT & MAT1A Low levels of SAM |
|
| D3 | High impact genetic variations in GNMT & VDR | D3 |
| Taurine |
High impact variation in CBS Low levels of taurine in blood |
Taurine 500 |
| Glutathione | High impact genetic variations in CTH, GSTM1, GSTP1, GSTT1, GPX1 | Liposomal Glutathione |
| Cysteine | High impact genetic variations in CBS & CTH | BioPure Protein with zinc |
| Zinc | High impact genetic variations in CBS & CTH | Zinc |
| Folate | Consider MTHFR, MTR, MTRR, MTHFD1 & DHFR | Folpro |
| Serine |
High impact in SHMT1 Poor serine/glycine levels |
BioPure Protein with zinc |
If you would like to sit down with me to plan how to achieve better methylation daily, or just to go over your methylation genotype; you can book a session online with me here:
I, my husband and two boys have really "wonky" methylation genes. Looking at them gives me anxiety (not that this is too hard for a poor methylator) but knowing this is so much more empowering than not knowing!
Marguerite Doig-Gander
CEO of MY DNA CHOICES
BA (Speech, Hearing & Lang Therapy) Hons | FMCHC | ReCODE Coach | Men's Health | HMX Genomics & Biochemistry (Candidate)
