One Carbon Metabolism in Cancer: Vital Pathways for Growth

Cancer cells require a constant supply of nutrients and biochemical building blocks to sustain rapid growth. One-carbon metabolism is a crucial network of reactions that provides essential molecules for nucleotide synthesis, amino acid metabolism, and methylation processes. This pathway integrates inputs from folate and methionine cycles to fuel biosynthetic and regulatory functions critical for cancer progression.

Given its role in cellular proliferation and epigenetic modifications, one-carbon metabolism has become a key focus in cancer research. Understanding how this system contributes to tumor development may reveal potential therapeutic targets that disrupt cancer cell survival while sparing normal tissues.

Primary Enzymes And Cofactors

One-carbon metabolism in cancer is driven by a network of enzymes and cofactors that facilitate the transfer of single-carbon units for biosynthesis and regulation. Serine hydroxymethyltransferase (SHMT) plays a central role by converting serine into glycine while transferring a one-carbon unit to tetrahydrofolate (THF), forming 5,10-methylenetetrahydrofolate. This reaction is a primary entry point for carbon units into the folate cycle, which is essential for nucleotide biosynthesis and methylation. SHMT exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms, with SHMT2 being particularly relevant in cancer cells due to its role in maintaining mitochondrial one-carbon flux under metabolic stress.

Dihydrofolate reductase (DHFR) sustains the folate pool by reducing dihydrofolate (DHF) to THF, ensuring a continuous supply of folate derivatives for cellular processes. Inhibitors of DHFR, such as methotrexate, are widely used in chemotherapy to disrupt nucleotide synthesis, highlighting the enzyme’s importance in cancer proliferation. Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary methyl donor for homocysteine remethylation to methionine. MTHFR gene variants have been linked to altered cancer risk due to their influence on methyl group availability for DNA and histone modifications.

Methionine adenosyltransferase (MAT) synthesizes S-adenosylmethionine (SAM), the universal methyl donor required for methylation reactions. Cancer cells often have an increased demand for SAM to support epigenetic modifications and polyamine synthesis, which contribute to tumor growth. The regulation of MAT activity is closely tied to methionine availability, and dietary methionine restriction has been explored as a strategy to impair cancer metabolism. Glycine N-methyltransferase (GNMT) modulates SAM levels by converting excess SAM into S-adenosylhomocysteine (SAH), preventing aberrant methylation that could disrupt cellular homeostasis.

Cofactors such as vitamins B6, B12, and folate are essential for these enzymes. Vitamin B6 acts as a coenzyme for SHMT, facilitating one-carbon transfers, while vitamin B12 is required for methionine synthase, which catalyzes homocysteine remethylation. Deficiencies in these vitamins can impair one-carbon metabolism, leading to disruptions in nucleotide synthesis and methylation that may contribute to tumorigenesis. The interplay between these cofactors and enzymatic activity underscores the metabolic flexibility of cancer cells, allowing them to adapt to nutrient availability and sustain rapid proliferation.

Folate And Methionine Cycles

The folate and methionine cycles are interconnected biochemical pathways that regulate the flow of one-carbon units essential for nucleotide biosynthesis and methylation. In cancer cells, these cycles are highly active to meet the increased demand for DNA replication and epigenetic modifications. The folate cycle begins with the conversion of dietary folate into tetrahydrofolate (THF), which serves as a carrier for one-carbon units. These carbon groups are processed through various folate intermediates, including 5,10-methylenetetrahydrofolate, which is critical for thymidylate synthesis, a necessary step in DNA replication. Cancer cells often upregulate enzymes involved in this process, such as SHMT and thymidylate synthase (TYMS), to ensure a steady supply of nucleotides for sustained growth.

5,10-methylenetetrahydrofolate can be reduced by MTHFR to form 5-methyltetrahydrofolate, the key methyl donor for the methionine cycle. This transformation influences the availability of methyl groups for DNA and histone methylation. The methionine cycle begins when 5-methyltetrahydrofolate donates a methyl group to homocysteine, catalyzed by methionine synthase (MS), yielding methionine. Methionine is then converted into S-adenosylmethionine (SAM), a universal methyl donor required for gene expression, chromatin structure, and protein function. Cancer cells frequently alter SAM metabolism to support oncogene activation or global hypomethylation, both of which contribute to tumor progression.

The balance between SAM and SAH is tightly regulated to prevent aberrant methylation. GNMT and adenosylhomocysteinase (AHCY) help maintain this equilibrium by converting SAH back into homocysteine, which can either be remethylated into methionine or directed toward glutathione synthesis. Some tumors, such as liver and colon cancers, exhibit methionine dependence, struggling to survive in methionine-depleted environments. This metabolic vulnerability has been explored as a therapeutic target, with dietary methionine restriction showing promise in preclinical models.

Links To Cell Growth

Uncontrolled proliferation is a hallmark of cancer, and one-carbon metabolism provides the biochemical resources necessary to sustain rapid expansion. The demand for nucleotides, amino acids, and methyl donors in tumor cells far exceeds that of normal tissues, requiring an efficient metabolic framework to support continuous division. One-carbon metabolism supplies purines and thymidylate, both essential for DNA replication. Without a sufficient nucleotide pool, cancer cells cannot progress through the cell cycle, making this pathway a fundamental driver of tumor growth. The upregulation of enzymes such as SHMT and TYMS reflects the heightened reliance on one-carbon metabolism, particularly in rapidly dividing malignancies like colorectal and breast cancers.

Beyond nucleic acid formation, this metabolic network influences amino acid homeostasis through serine and glycine metabolism. Serine contributes carbon units to the folate cycle, while glycine serves as a building block for proteins and glutathione, a critical antioxidant that protects cancer cells from oxidative damage. The ability to maintain redox balance is particularly advantageous in the tumor microenvironment, where fluctuating oxygen levels and metabolic stressors create conditions that would otherwise limit proliferation.

Methylation dynamics further illustrate the connection between one-carbon metabolism and cancer growth. SAM ensures a steady supply of methyl groups for histone and RNA modifications, both of which regulate gene expression. Some tumor types, including pancreatic and prostate cancers, exhibit heightened reliance on external methionine sources, making them particularly susceptible to dietary interventions that disrupt one-carbon metabolism.

Influence On DNA Methylation

DNA methylation is closely linked to one-carbon metabolism, as the availability of methyl donors directly impacts the epigenetic landscape of cancer cells. DNA methylation, primarily occurring at cytosine residues within CpG dinucleotides, is catalyzed by DNA methyltransferases (DNMTs) using SAM as the methyl donor. The balance between SAM and SAH dictates methylation efficiency, with elevated SAH levels inhibiting DNMT activity. Disruptions in this balance contribute to aberrant methylation patterns in tumors, where promoter hypermethylation silences tumor suppressor genes while global hypomethylation destabilizes genomic integrity.

Cancer cells frequently exhibit a reprogrammed methylation profile that enhances their proliferative capacity. Specific tumor types, such as colorectal and lung cancers, carry hypermethylated promoters in genes regulating apoptosis and cell cycle control, effectively shutting down critical regulatory mechanisms. Conversely, widespread hypomethylation can activate oncogenes or promote chromosomal instability, facilitating malignant transformation.

Role In Cancer Cell Metabolism

One-carbon metabolism is embedded in the metabolic reprogramming of cancer cells, providing essential precursors for biosynthesis while enabling adaptations that support survival. Cancer cells frequently enhance mitochondrial one-carbon metabolism, particularly through SHMT2, which facilitates the production of formate, a key intermediate sustaining nucleotide biosynthesis and redox balance. Elevated formate levels have been detected in various tumors, ensuring a continuous supply of one-carbon units necessary for proliferation.

The oxidation of one-carbon units within the mitochondria generates NADPH, a reducing agent vital for counteracting oxidative stress. Given this dependency, inhibitors targeting mitochondrial one-carbon metabolism, such as SHMT2 and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), have been investigated as potential therapeutic strategies.

Interactions With Other Metabolic Networks

One-carbon metabolism intersects with multiple metabolic networks that sustain tumor progression. Its integration with glycolysis and the tricarboxylic acid (TCA) cycle is particularly significant, as cancer cells must efficiently allocate carbon sources to balance energy production and biosynthesis. Many cancer types, including breast and melanoma, exhibit PHGDH amplification, reinforcing the connection between glycolytic flux and one-carbon metabolism.

Lipid metabolism also intersects with one-carbon metabolism, as SAM availability influences phospholipid methylation, necessary for maintaining membrane integrity and signaling functions. The interconnected nature of these pathways underscores the complexity of cancer metabolism, presenting multiple potential targets for therapeutic intervention.