Methionine – a crucial amino acid in metabolism, antioxidant defense, and cellular function

• History & Evolution
• Biosynthesis vs. dietary uptake
• Methionine and the microbiome
• Methionine and DNA methylation
• Methionine and cardiovascular disease
• Methionine and neurogenerative disorders
• Methionine and cancer

History & Evolution

1921: discovery (Mueller, J., 1921) | 1928: structure identified (Barger, G., 1928) | 1945-7: first synthesis (Livak, J. et al., 1945).

Methionine’s story begins just over a century ago, when it was discovered in casein by JH Mueller in 1921 (Mueller, J., 1921). In 1928, Barger and Coyne determined the chemical structure of what was until then known as γ-methylthiol-α-aminobutyric acid and suggested a more straightforward name: methionine (Barger, G., 1928). By the 1930s, methionine was recognized as an essential and limiting amino acid involved in protein synthesis, with subsequent research focusing on its vital role in human and animal diets (Rose, W., 1976). In the aftermath of World War II, protein shortages and widespread malnutrition prompted the hunt for a synthetic form of methionine (Livak, J. et al., 1945).

Now, over one million tons of methionine are produced each year from petroleum, with many applications including poultry feed, flavor enhancers, cosmetics, drugs and pesticides (Neubauer, C., 2021).

Methionine is found in humans, animals, plants and bacteria. In humans, methionine has been described as a “double-edged sword” (Navik, U. et al., 2021). It plays a crucial role in cellular, metabolic, epigenetic and genomic processes, influencing a broad range of physiological functions. It has been shown to support immune function, digestion, insulin resistance, to extend lifespan, and to reduce DNA damage and carcinogenesis (Martínez, Y. et al., 2017). However, excessive amounts can be toxic, with adverse effects including increased cholesterol and hyperhomocysteinemia (Navik, U. et al., 2021); (Garlick, P., 2006).

There is a theory that not only is this ancient metabolite essential for life, but – as a self-activating and sulfur containing amino acid – it may have triggered the development of life on Earth itself (Heinen, W., 1996).

Biosynthesis vs. dietary uptake

As an essential amino acid, methionine must be obtained via the diet and gut microbiota (Parkhitko, A. et al., 2019). Primary dietary sources of methionine include eggs, fish, meat, dairy and plant protein sources (Navik, U. et al., 2021) (Rajavel, E., 2020). In bacteria, methionine is synthesized from cysteine and aspartic acid. Plasma methionine concentration in healthy subjects ranges from 13 to 45 µM (Navik, U. et al., 2021).

The Quantitative Metabolomics Database (QMDB), cataloguing the concentrations of over 600 metabolites in healthy individuals reports average levels of 28 µM for women and 30 µM for men.

Methionine is one of four sulfur-containing amino acids, and, along with cysteine, one of two incorporated into proteins (Brosnan, T., 2006). Daily dietary requirements for methionine are usually taken together with cysteine, and the total sulfur amino acid requirement (TSAA) is 13-15 mg/kg/d for adults (Rajavel, E., 2020).

Methionine metabolism involves three key stages (Parkhitko, A. et al., 2019); (Lauinger, L., 2021):
– the methionine cycle,
– the transsulfuration/transmethylation pathway
– the methionine salvage cycle

In the methionine cycle, methionine and adenosine triphosphate (ATP) are converted into the methyl donor S-adenosylmethionine (SAM) by the enzyme methionine adenosyltransferase. After transferring the methyl group, SAM is converted to S-adenosylhomocysteine (SAH) and hydrolyzed into adenosine and homocysteine. This homocysteine can be remethylated to methionine by the methionine synthase enzyme (with vitamin B12 as a coenzyme), which completes the cycle, or diverted to the transssulfuration pathway to form cysteine (Rajavel, E., 2020); (Parkhitko, A. et al., 2019). In the salvage cycle, methionine is regenerated from decarboxylated SAM, following a series of enzymatic steps involving polyamine synthesis.

Methionine is a precursor to other molecules including antioxidants such as glutathione and cystathionine, and amino acids including cysteine, carnitine, taurine and creatine (Navik, U. et al., 2021).

Methionine and the microbiome

Gut microbiota play a major role in methionine metabolism, with around 20% of dietary methionine metabolized in the gut (Wu, X. et al., 2022); (Bauchart C. et al., 2009). In turn, methionine metabolism influences gut health, as evidenced by the interactions between methionine levels, microbial composition and disease states.

A multi-omics study comparing vegan and omnivore diets found that methionine positively correlates with Bacteroides, Blautia, Dorea, Lachnoclostridium and Fusicatenibacter, with all except Bacteroides being more abundant in omnivores (Prochazkova, M. et al., 2022). Another study found that restricting sulfur amino acids like methionine increases the abundance of Firmicutes, Clostridaceae and Turicibacteraceae, while decreasing Verrucomicrobia, compared to a low-calorie diet (Nichenametla, S. et al., 2021). These findings show how methionine intake influences the diversity and abundance of bacterial species in the gut.

Animal studies have shown that restricting dietary methionine, e.g. through a plant-based diet, may improve gut health. Methionine restriction in mice was found to increase short chain fatty acid (SCFA)-producing bacteria such as Bifidobacterium, Lactobacillus, Bacteroides, Roseburia, Coprococcus, and Ruminococcus, and increase inflammation-inhibiting bacteria like Oscillospira and Corynebacterium (Yang, Y. et al., 2019). In contrast, the high fat diet reduced SCFA production and induced gut dysbiosis.

Methionine appears to play a role in several inflammatory diseases associated with disrupted gut microbiota (Wu, X. et al., 2022). For example, a study in patients with inflammatory bowel disease (IBD) showed reduced levels of methionine, serine and sarcosine, along with fewer SCFA-producing gut bacteria (Borren, N. et al., 2021). Another study found changes in methionine and homoserine levels in patients with Parkinson’s disease (PD) (Hertel, J. et al., 2019). PD patients showed an increase in Akkermansia muciniphila, which is involved in sulfur metabolism. This contributed more than 70% of potential methionine production, suggesting a clear link between gut microbiota and the methionine cycle (Wu, X. et al., 2022).

Methionine and DNA methylation

Methionine is essential for DNA methylation, a key epigenetic mechanism affecting gene expression related to growth and development (Lauinger, L., 2021). In this process, DNA methyltransferases transfer a methyl group from SAM to the C-5 position of the pyrimidine ring of cytosine (Jin, B. et al., 2011). Changes in dietary methionine change the ratio of SAM to SAH (the “methylation index”), which influences methylation capacity. This can be measured using immunoassays to detect levels of SAM and SAH in blood and tissue (Hao, X. et al., 2016).

Dysregulation of DNA methylation is associated with some cancers (Bauchart C. et al., 2009). Studies suggest that methionine supplementation can affect DNA methylation, with both positive and negative effects depending on the gene region affected (Waterland, R., 2006).

More research is needed to fully understand methionine’s role in DNA methylation. Metabolomics offers a useful tool with which to understand epigenomics and DNA methylation in more detail, especially when combined with other omics. For example, a 2020 study combined metabolomics, proteomics and genomics to show that activated T cells use methionine to synthesize SAM, identifying methionine as a key nutritional factor in shaping T helper cell activity through histone methylation (Roy, D. et al., 2020). The findings suggest restricting dietary methionine could be a viable intervention in the treatment of autoimmune conditions such as multiple sclerosis.

Layering insights from different omics analyses in this way gives a fuller picture of the interactions between metabolites, proteins, genes and environmental factors that drive disease processes.

Methionine and cardiovascular disease

Too much methionine may increase the risk of cardiovascular disease (CVD). Methionine is involved in DNA synthesis, lipid regulation, oxidative defense and cellular regulation – processes all thought to play a role in CVD and other diseases (Aissa, A. et al., 2017). Impaired DNA methylation may also be a factor, as this increases circulating LDL cholesterol and lowers HDL cholesterol, both of which are risk factors for CVD (Calderón, A. et al., 2020); (Blachier, F. et al., 2020).

Another key mechanism is linked to methionine’s downstream metabolite homocysteine, which is known to be vasotoxic (Troen, A. et al., 2003). In excess, homocysteine can cause hyperhomocysteinemia, which is a well-established risk factor for CVD. A longitudinal population-based study found that a lower concentration of methionine, higher concentration of homocysteine and lower ratio of methionine to homocysteine were associated with an increased risk of CVD (Calderón, A. et al., 2020).

Excess methionine may also damage endothelial cells and increase plasma lipid levels, which both contribute to atherosclerosis. High levels of dietary methionine have been found to increase the risk of acute coronary events in middle-aged men (Virtanen, J. et al., 2006).

By contrast, methionine restriction appears to delay development of CVD and associated risk factors such as obesity (Zhang, Y. et al., 2022).

Methionine and neurogenerative disorders

Excess methionine is linked to neurodevelopmental disorders, like autism and schizophrenia, and neurodegenerative disorders such as Alzheimer’s disease (AD) and PD (Alachkar, A. et al., 2022); (Hertel, J. et al., 2019). A 2023 study involving animal and human AD phenotypes found that methionine intake is associated with mild cognitive impairment, and methionine restriction improves cognitive function (Xi, Y. et al., 2022).

More research is needed to understand the mechanisms, but again, methionine’s role in DNA methylation and homocysteine production may be relevant. A population-based study found links between methionine, homocysteine and dementia development, suggesting that a higher methionine to homocysteine ratio may reduce brain atrophy and lower the risk of dementia (Hooshmand, B. et al., 2019).

As noted above, a longitudinal metabolomics study investigated links between PD, sulfur metabolism and the gut microbiome (Hertel, J. et al., 2019). This showed differences between methionine and cysteine production via cystathionine in PD patients and healthy subjects. Using multiomics, the researchers were able to identify patterns in microbial-host sulfur metabolism that may contribute to PD severity.

Methionine and cancer

Methionine restriction is also an “exciting potential tool in the treatment of cancer” (Wanders, D. et al., 2020). Methionine inhibits cancer cell proliferation and growth in several types of cancer, without damaging healthy cells (in the presence of homocysteine). It also appears to improve efficacy of chemotherapy and radiation therapy in animal models. A 2020 review summarized evidence showing that methionine restriction could inhibit cancer development and/or progression in prostate cancer, breast cancer and colorectal cancer (Wanders, D. et al., 2020). Possible mechanisms vary by cancer type. It may be that methionine restriction inhibits polyamine biosynthesis, induces apoptosis, alters DNA methylation and glutathione formation, and reduces activity of thymidylate synthase, the enzyme that converts dUMP to dTMP.

 
More about the Metabolite of the Month
Reference ranges of methionine in healthy humans
Quantify the impact of methionine