This summary was put together based on a wide variety of public information, much of it from Wikipedia. Certain sections of the summary below borrow heavily from the podcast “The Drive with Peter Attia — Chris Masterjohn“ where methylation is discussed in detail (the episode is worth your time and the show-notes of the episode contain a lot of helpful information). Methylation is a very complicated subject and affects many processes in the human body. I have tried to highlight some of the relevant details of the basic process and helpful takeaways (primarily, what makes sense to scan for if you want to explore the health of your methylation cycle) . Any mistakes in the summary below are mine.

Summary

• Introduction.
• Purpose of Methylation.
• Methylation Cycle: Methionine to Homocysteine.
• Methylation Cycle: Breakdown of Homocysteine.
• Methylation Cycle: Homocysteine Back to Methionine.
• Pathway 1: Folate (Methionine Synthase).
• Pathway 2: Choline (BHMT).
• High Homocysteine.
• Relevant Enzymes.
• Key Takeaways.

Introduction

• To methylate = “to put on a methyl group”
  • Methyl group consist of one carbon and three hydrogen atoms (CH3).
    • One carbon unit = methyl groups.
    • Two carbon units = acetyl groups.
  • In a biochemical process, a methyl group is transferred to a substrate.
    • Substrates: DNA, neurotransmitters, hormones, immune cells or nerve cells.
  • The newly formed compounds go on to perform many tasks in the body.
• Methylation cycle:
  • ATP activates methionine to donate its methyl group and form SAM.
  • SAM is the universal methyl donor to many cellular functions.
  • Homocysteine is the inevitable end-product after SAM donates its methyl group.
  • Once formed, homocysteine is broken down or recycled back to methionine.
  • Process starts again.
• Complicated process.
  • The process relies on and involves many co-factors and genese/enzymes.
    • Co-factors include folate (B9), choline (B4), B2, B6 and B12.
    • Genes/ Enzymes include MTHFR, MTRR, MTR and MAT.
• Methylation imbalances.
  • Inadequate dietary intake or absorption of nutrients.
  • Bad SNPs.
  • Lifestyle (smoking, alcohol, stress)

Purpose of Methylation

• Synthesis creatine and phosphatidylcholine.
  • Represents about 90% of the methylation process.
• Remaining 10% of methyl acceptors spread across dozens of reactions.
  • Breakdown of dopamine and other neurotransmitters.
• Most sensitive to methylation is dopamine.
  • If dopamine is methylated (broken down), you are more flexible.
  • If dopamine is not methylated, you are more stable.
  • COMT is the enzyme involved in dopamine methylation.
  • Lower COMT activity results in higher levels of dopamine (worrier type).
• Specific methylation related tasks:
  • Repairing and regenerating your cells, tissues and DNA.
  • Regulating gene expression and protein function.
  • Synthesizing neurotransmitters that influence mood, sleep, behavior, cognition and memory.
  • Controlling homocysteine.
  • Keeping inflammation in check.
  • Assisting your liver in processing fats.
  • Activating and regulating the immune system.
  • Modifying toxins and heavy metals.

Methylation Cycle: Methionine to Homocysteine

• Cycle starts with amino acid methionine.
  • Comes from your dietary protein.
• First step is to activate methionine:
  • This requires ATP and magnesium.
• Methionine -> SAM.
  • Turn methionine into to S-Adenosyl methionine (SAM or SAMe)
  • SAM is the universal methyl donor.
  • No matter what is regulated, SAM will donate the methyl group.
• SAM -> SAH.
• SAH -> homocysteine.
• From homocysteine, two pathways:
  • Broken down.
  • Recycled back to methionine.

Methylation Cycle: Breakdown of Homocysteine

• Homocysteine -> Cysteine.
  • • Using vitamin B6 and serine or glycine.
• Cysteine -> taurine, sulfate or glutathione.
  • Taurine: electrical activity in the brain and retina.
  • Sulfate: regulating hormones and promoting detoxification and other uses.
  • Glutathione: antioxidant, detoxification, protects from oxidative stress, etc.

Methylation Cycle: Homocysteine Back to Methionine

• Homocysteine -> methionine.
• Supported by two pathways:
  • Folate (vitamin B9):
    • Provides methyl group to B12.
    • B12 then passes it onto homocysteine.
    • Homocysteine regenerates methionine
  • Choline (vitamin B4):
    • Oxidized to betaine.
    • Betaine is a methyl donor to recycle homocysteine to methionine.
• Half of methylation is supported by folate (and B12), half by choline (or betaine).

Pathway 1: Folate (Methionine Synthase)

• Driven by:
  • Folate (B9).
  • B12.
  • MTHFR SNP.
• How methyl groups get donated:
  • Folate / folic acid -> tetrahydrofolate (THF).
  • THF -> 5,10-methylene THF.
  • 5,10-methylene THF -> 5 MTHF:
    • Requires the MTHFR enzyme and vitamin B2.
  • 5 MTHF + B12 -> methylcobalamin.
  • Methylcobalamin + homocysteine -> methionine.
• Folate / folic acid:
  • Folate: naturally occurring form .
    • Sources: asparagus, avocados, dark leafy vegetables..
  • Folic acid: a synthetic form, also known as pteroylmonoglutamic acid.
    • Used to make supplements.
• B12:
  • Most chemically complex of all vitamins.
    • Sources: Liver and shellfish (clams, oysters), eggs, and dairy products.
    • Plants don’t make vitamin B12.
•  MTHFR:
  • Up to 50% of the population may be affected by a MTHFR gene variance.
  • MTFHR variance may lead to impaired ability to process folate.
  • Leads to more limited ability to produce 5-MTHF.
  • Leads to build-up of homocysteine, inadequate production of methionine.
  • May make sense to supplement with L-5-methyltetrahydrofolate,
    • Skips directly to the ‘last step’ of the folate pathway.
  • Or improve choline pathway.

Pathway 2: Choline (BHMT)

• Driven by:
  • Choline (B4)
• Choline has many purposes.
  • Structural integrity of cell membranes.
    • Synthesis of phospholipids, such as Phosphatidylcholine (PC).
    • PC is an essential component of cell membranes.
  • Cell signaling.
  • Nerve impulse transmitter.
    • Precursor of acetylcholine.
    • Acetylcholine is involved in muscle control, circadian rhythm, memory, etc.
  • Lipid transport and metabolism.
    • PC needed for VLDL, LDL synthesis in the liver.
    • Without adequate PC, fat and cholesterol accumulate in the liver.
  • Source of methyl groups.
    • Choline oxidizes to form betaine.
    • Betaine provides up to 60% of methyl groups for methylation of homocysteine.
• And is derived from various sources:
  • From PC.
    • PC synthesis requires:
      • Catalyzation by PEMT.
      • Methyl groups donated by SAMe.
    • Limited amounts of choline may then be generated out of PC.
  • From diet.
    • De novo generation of choline (from PC) not sufficient.
    • Foods: liver, egg yolk, spinach, salmon, cod, broccoli, cauliflower.
  • Through supplements.
    • Citicoline (CDP-choline).
    • CDP-choline is an intermediate in the synthesis of phospholipids.
• Choline pathway:
  • Choline -> betaine.
  • Betaine + homocysteine -> methionine.

High Homocysteine 

• Genetic issue.
  • Conversion back to methionine or breakdown highly dependent on sufficient b vitamins being available.
  • Genetic issues may be related to (bad) B vitamin absorption or processing.
    • FUT2 gene: absorption of B12 vitamin.
    • MTHFR gene: conversion of B9 vitamin.
    • MTRR gene: folate pathway efficiency.
• High homocysteine may cause:
  • Oxidation injuries:
    • Damage to the arteries.
    • Interfering with the way cells use oxygen, resulting in a build-up of damaging free radicals.
    • Free radicals can oxidize LDL particles, producing oxy-cholesterols and oxidized fats and proteins within developing arterial plaques.
    • Triggers many diseases including heart disease, strokes, cancers and autoimmune diseases.
  • Disrupting nitric oxide metabolism:
    • Important regulator and mediator of numerous processes in the nervous, immune and cardiovascular systems
  • Decreased methylation:
    • Impaired DNA repair.
    • Caused by disturbances in the folate processing.
    • Contributes to carcinogenesis.
  • Growth of smooth muscle cells:
    • Causes a thickening and hardening of artery walls.
• Potential fixes:
  • Improve homocysteine conversion back to methionine:
    • Folate pathway:
      • Increase folate, supplement or food (dark leafy greens, liver, avocado, asparagus, broccoli, and lentils)
      • Increase B12, supplement or food (liver, eggs, nuts, beans)
      • Activate MTHFR through co-factor vitamin B2 (riboflavin) – stabilizing the enzyme and increasing its efficiency.
    • Choline pathway:
      • Increase choline, supplement or food (see above).
      • Increase betaine, supplement or food (quinoa, spinach, beets).
  • Improve homocysteine breakdown:
    • Increase vitamin B6, glycine.
  • Remove inhibiting compounds:
    • Heavy metals, solvents, chemicals, toxins.
• Life style factors that may affect homocysteine:
  • Poor diet, smoking, high coffee and alcohol intake, some prescription drugs, diabetes, rheumatoid arthritis and poor thyroid function.
  • Obesity and lack of exercise.
  • Chronic inflammatory diseases in general.
  • Higher levels are more common in men than women

Relevant Enzymes.

• MTHFR.
  • Synthesis of 5MTHF.
• MTR and MTRR.
  • Folate pathway.
• MAT.
  • Synthesis of SAM.
• BHMT.
  • Choline pathway.
• CBS.
  • Homocysteine breakdown.

Key Takeaways

• Check genetic profile: check methylation-related SNPs for shortfalls in key enzymes, substrate issues, etc.).
• Check nutrients: specifically levels of relevant B vitamins.
• Check relevant metabolites: homocysteine, SAM, SAH.