Why the “Methylation Cycle” Is Not Just About Folate or Vitamin B12

When people hear methylation, they often think about folate or vitamin B12 supplements. While these nutrients are important, this framing misses the much bigger—and far more powerful—biological story.

At its core, the methionine cycle is the cell’s methyl-production and regulation system. It governs how genes are turned on or off, how proteins function, and how cells decide between growth, repair, and defense. Even more importantly, this cycle is directly connected to redox balance through the transsulfuration pathway, which fuels glutathione, the body’s primary antioxidant.

A recent large study published in PNAS makes this broader picture impossible to ignore.

What the New COVID-19 Study Found

In a 2025 PNAS paper, Petrova et al. analyzed blood samples from over 1,000 hospitalized COVID-19 patients using genomics and metabolomics. Their key finding was striking:

Disruption of one-carbon metabolism—specifically the methionine cycle—strongly predicted COVID-19 severity and long-COVID risk.

Importantly, the strongest signals were not simple vitamin deficiencies. Instead, the markers that mattered most were:

• Methionine oxidation products

• S-adenosylhomocysteine (SAH), a brake on methylation

• Altered redox-sensitive sulfur metabolites

Patients carrying a common MTHFR genetic variant were more vulnerable—but genetics alone did not determine outcomes. Risk emerged when genetic predisposition and early metabolic imbalance occurred together.

This tells us something fundamental: the problem was not “low folate,” but a failure of coordinated methylation and redox regulation 

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The Methionine Cycle: The Cell’s Instruction-Writing System

The methionine cycle produces S-adenosylmethionine (SAM)—the universal methyl donor. SAM is required for:

• DNA methylation (epigenetic regulation)

• RNA methylation

• Protein methylation (affecting structure, signaling, and enzyme activity)

• Neurotransmitter and phospholipid synthesis

In simple terms:

Methylation is how cells write, edit, and protect their instruction manual.

When methylation capacity is impaired, gene expression becomes unstable, stress responses become exaggerated, and recovery slows—even if vitamins appear “normal” on standard labs.

Transsulfuration: Where Survival Meets Antioxidant Defense

The story doesn’t stop at methylation.

The methionine cycle is tightly linked to transsulfuration, a pathway that converts homocysteine into cysteine, the key building block for glutathione (GSH).

Glutathione is essential for:

• Neutralizing oxidative stress

• Supporting immune activation

• Protecting mitochondria

• Resolving inflammation

This creates a built-in biological trade-off:

• More methylation → supports gene regulation and repair

• More transsulfuration → supports antioxidant defense and survival under stress

During infection, inflammation, or chronic stress, the body often shifts toward glutathione production, temporarily sacrificing methylation capacity. When this state persists, epigenetic dysregulation and redox imbalance occur together.

This is exactly what the COVID-19 study observed: redox-modified methionine metabolites—not vitamin levels—tracked with worse outcomes.

The Big Picture: Homeodynamic Balance, Not Vitamin Deficiency

What this research reinforces is a critical concept:

The methionine–transsulfuration network is a central homeodynamic axis linking gene expression, redox balance, immune resilience, and recovery.

Framing this system as merely a “folate” or “B12” cycle dramatically underestimates its role. Vitamins are necessary inputs—but the system’s failure reflects chronic energetic stress, inflammation, oxidative load, and impaired resolution, not simple nutrient absence.

This is why some people with “normal” labs still experience fatigue, brain fog, slow recovery, or long COVID.

Why This Matters Beyond COVID

Although this study focused on COVID-19, the implications are broader:

• Chronic stress

• Autoimmune disease

• Aging

• Neurodegeneration

• Burnout and post-viral syndromes

All involve the same methylation–redox trade-offs. Recovery is not just about adding nutrients—it’s about restoring metabolic flexibility and resolution capacity.

Takeaway

The methionine cycle is not a vitamin pathway.

It is a decision-making system that determines whether cells invest resources in:

• writing and stabilizing genetic instructions, or

• defending against oxidative and inflammatory threats.

When this balance is lost, health declines—not because the body is broken, but because it is over-adapted and under-recovered.

Understanding this helps shift medicine from “deficiency correction” toward restoring biological resilience.

Petrova, B., Syphurs, C., Culhane, A. J., Chen, J., Chen, E., Cotsapas, C., Esserman, D., Montgomery, R. R., Kleinstein, S. H., Smolen, K. K., Mendez, K., IMPACC Network, Lasky-Sub, J., Steen, H., Levy, O., Diray-Arce, J., & Kanarek, N. (2025). MTHFR allele and one-carbon metabolic profile predict severity of COVID-19. Proceedings of the National Academy of Sciences of the United States of America, 122(51), e2509118122. https://doi.org/10.1073/pnas.2509118122