What is methylation?

What is methylation?

Margie GanderApr 8, '20

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 complexed. And important. But unless we completely understand it's a 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:

  1. SAM/SAH
  2. Un-methylated metabolites/Methylated metabolites 
  3. 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

PEMT

BHMT-02

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

CBS

AHCY

CTH

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

GNMT

SHMT1

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 

CBS

CTH

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

CTH

CBS

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

 

MTHFR

DHFR

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

Methylation Support

MethylCare

Choline Supports PEMT & BHMT genetic variations that reduce the bioavailability of 

phosphatidylcholine

Low levels of choline in the blood

 

Methylation Support

B-complex Methylated

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

Magnesium

Magnesium Glycinate

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)   

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