Methion, also known as Methionine, is one of the essential amino acids for the human body and one of the two sulfur-containing amino acids in the human body (the other is cysteine).This review aims to comprehensively summarize the methionine metabolic pathway, explore its function under normal physiological conditions, and its role in different pathological states. We will conduct an in-depth analysis of the key components, regulatory mechanisms and metabolic pathways of methionine metabolism, especially its importance in health, aging and various diseases.
Where Does Methionine Come From
Methine, chemically named 2-amino-4-methylmercaptobutyric acid, is an essential sulfur-containing amino acid and ketogenic amino acid in mammals. Methine is rich in egg protein and casein. The natural form is L. Both L and D are effective, but the bioavailability of L is higher than that of D.
The human organism lacks the biological machinery to produce methionine endogenously, necessitating its acquisition through dietary sources. Among animal-derived foods, dairy products such as cheese and particularly egg albumin contain substantial concentrations of this amino acid, while marine life and poultry serve as excellent sources as well. Notable among plant-based options, marine algae stands out with exceptional methionine levels compared to other vegetables. When dietary intake proves insufficient, protein biosynthesis becomes compromised, manifesting in symptoms including diminished appetite, developmental delays, and reduced body mass. Severe deficiency states can result in significant organ dysfunction, particularly affecting the kidneys through enlargement and the liver via iron deposition, potentially progressing to hepatic fibrosis or necrotic changes. Supplemental methionine intake may become necessary under specific circumstances, including hepatic insufficiency, extensive muscular breakdown, or states of extreme physical fatigue.
Metabolic Pathways of Methionine
The Methionine Cycle
In the organism, methionine first accepts the adenosine group from ATP and is quickly transformed into the central one-carbon cycle metabolite S-adenosylmethionine (SAM). SAM is the main methyl donor and is necessary in the metabolism of DNA, proteins and lipids. After methyl transfer, S-adenosyl homocysteine (SAH) is hydrolyzed into adenosine and homocysteine (Hcy) by SAH hydrolase; Hcy uses 5-methyltetrahydrofolate (5-MTHF) as a methyl donor, and is remethylated by Hcy methyltransferase to complete the methionine cycle. In addition to 5-MTHF, Betaine or thiobetaines can also be used as a methyl donor. In addition, vitamin B12 is also necessary for the Hcy remethylation step in mammals.
In addition to producing the main methyl donor, methionine is also indirectly involved in the synthesis of polyamines, which are crucial for cell growth. Decarboxylated SAM (dcSAM) is the donor of the aminopropyl group. After the aminopropyl group is transferred, dcSAM is converted to 5-deoxy-5-methylthioadenosine (MTA), which is then recycled to regenerate adenine and methionine through the methionine recovery pathway.
Figure 1. Methionine metabolic pathways.
Methine is a sulfur-containing amino acid that is closely related to the metabolism of various sulfur-containing compounds in organisms. Methion can maintain the redox state of cells through the transsulfur pathway using Hcy as a substrate. Hcy is converted to cysteine (Cys) through cystathionine, which is further converted to reduced glutathione (GSH) and taurine (Taurine);GSH scavenges reactive oxygen radicals and is reversibly oxidized to oxidized glutathione (GSSG). The difference between mammals and yeast is that the former converts Hcy to Cys is one-way, while the latter can convert Cys to Hcy through a reverse reaction.
The Transsulfuration Pathway
In most fungi, methionine can be produced through the sulfur assimilation pathway. Sulfate is reduced to sulfite and eventually converted to sulfide. Hcy is synthesized from sulfides such as O-acetyl homoserine, and then Methylated through the folic acid cycle, ultimately yielding methionine. This process requires energy, with each methionine molecule consuming 2 ATP and 4 NADPH molecules.
Methionine Metabolic Functions
The primary function of methionine metabolism in organisms is as a methyl donor, and SAM is an essential substrate for all methylation reactions, including the methylation of DNA, RNA and histones to regulate epiinheritance. SAM also has an important impact on polyamine synthesis and phospholipid metabolism to maintain the stability of proteins, DNA and RNA, protect cells from oxidative stress, and regulate ion channel activity. In addition, SAMTOR protein can specifically play the role of SAM sensor under low methionine conditions, inhibit the activity of nutrient sensing protein mTORC1, and regulate cell metabolism, proliferation and autophagy.
In addition to its biological role through SAM-dependent reactions, methionine directly participates in the folic acid cycle through Hcy, providing raw materials for the biosynthesis of purines and pyrimidines. The adenine generated in the recovery path provides another substrate for purine metabolism; Through the reversible oxidation of GSH to GSSG, it protects against cellular oxidative stress damage caused by ROS and serves as a regulator of cellular oxidative stress; in addition, methionine also provides a source of sulfur in the generation of the key gas signaling molecule H2S.
Figure 2. Role of methionine in biological processes. (Sanderson, S.M., et. al, 2019)
Based on the above-mentioned physiological functions of methionine, it plays an important role in maintaining the body's metabolic stability, promoting body growth and development, and regulating the body's immune system. Therefore, methionine is used in the medicine, food, beauty, and feed industries. It has applications.
Pharmaceutical field: Methionine is one of the main components of amino acid infusions and can also be used to synthesize medicinal vitamins; its antioxidant effect promotes fat metabolism in the liver. It can be used as a liver protection preparation and a cholagogue for acute and chronic hepatitis, fatty liver, liver cirrhosis and cholestasis caused by various reasons; its methylation is used to detoxify and can be used for auxiliary treatment of poisoning by chemical substances such as sulfanilamide drugs, arsenic, and benzene.
Other applications: Methionine can be added to food to improve the balance of amino acids and used as a nutritional supplement; it can promote the synthesis of skin collagen and keratin, while improving sleep quality and immune function, and achieve the effect of comprehensively improving skin health; In the feed industry, methionine, as a nutritional enhancer for protein feeds and a nutritional additive to balance amino acids, has the effects of promoting the growth of livestock and poultry, increasing lean meat, and shortening the feeding cycle.
Regulation of Methionine Metabolism
Regulation of methionine metabolism is a complex process involving multiple enzymes, molecular mechanisms and regulatory pathways. By accurately controlling the rate of methionine metabolism, cells can ensure steady state during physiological processes and cope with different physiological and pathological conditions.
Regulation of enzymes
Key enzymes involved in methionine metabolism include MAT (methionine adenosyltransferase), SAHH (S-adenosyl homocysteine hydrolase), MTR (methyltransferase) and CBS (cysteine beta-synthase). These enzymes play a crucial role in different links of the metabolic pathway, and their activities are regulated by multiple factors.
MAT is a key enzyme in methionine synthesis, converting methionine to SAM. SAM is the most important methyl donor in the body and is involved in the methylation modification of DNA, RNA, proteins and lipids. The activity of MAT is affected by the concentration of the substrates methionine and ATP, as well as the participation of the cofactor vitamin B12.
Figure 3. Control of mating type specific genes. (Haber J. E., et. al, 2012)
SAHH produces Hcy and adenosine by hydrolyzing SAM, which is an important feedback inhibitor of methionine metabolism. Hcy is one of the main causes of homocysteinemia, and its accumulation can lead to metabolic disorders.
Molecular mechanism
The regulation of methionine metabolism not only depends on the direct action of enzymes, but is also influenced by specific genes and signaling pathways.
Transcriptional regulation: The expression of methionine synthetase (such as MAT) and cysteine β-synthase (such as CBS) is regulated by transcription factors. For example, MAT expression is regulated by vitamin B12 levels, while CBS expression is regulated by multiple signaling pathways.
Post-translational modifications: The activity of methionine metabolizing enzymes can be regulated through post-translational modifications such as phosphorylation. For example, the phosphorylation state of MAT affects its activity and stability.
Feedback inhibition: The feedback inhibition mechanism in methionine metabolism ensures the steady state of the metabolic process. For example, high concentrations of SAM inhibit MAT activity, thereby reducing SAM production.
Allosteric effectors: Certain metabolites (such as Hcy) can act as allosteric effectors to regulate the activity of MAT and other related enzymes.
Methionine Restriction and Anti-Tumor
Although methionine is crucial to human health, intake should be moderate and excessive amounts can pose health risks. Many studies have shown that diet restricted through methionine (or MR diet) is associated with improving health, extending life, reducing obesity induced by a high fat diet, and preventing diabetes. The figure below models the relationship between dietary intake of methionine and age, and takes into account the increased need for methionine in early development compared to the amount needed by adults to maintain physiological processes.
Figure 4. Dietary methionine intake has age-dependent effects on health. (Sanderson, S.M., et. al, 2019)
Research at the University of Tokyo showed that restriction on methionine intake in early adulthood in fruit flies dropped to 10% of that in the control group for 4 weeks, and the average life span of female fruit flies increased by 34.5%, suggesting that MR may have potential benefits in extending life(Kosakamoto, H.,et.al,2023). A recent research team at Duke University in the United States also confirmed this result: When MR is performed in early adulthood in fruit flies at 10% of the standard concentration, the best life extension effect can be achieved, but intervention is ineffective later in life. These observations provide evidence for the link between dietary amino acid composition and long-term health maintenance, and further support that "MR diet may have therapeutic benefits in certain diseases, such as cancer."
Tumor microenvironment
In the tumor microenvironment, methionine is also crucial for the growth and survival of non-tumor cells. As a key component of anti-tumor immunity, T cells require a continuous supply of exogenous methionine for their proliferation and activation. Therefore, methionine metabolism can also affect tumor growth and progress by regulating anti-tumor immunity mediated by immune cells. Accordingly, the impact of MR on tumor growth and treatment response depends not only on the dependence of the tumor cells themselves on methionine, but also on the relative dependence of cancer cells and T cells on methionine in the tumor microenvironment. In healthy people or early-stage cancer patients, T cells are more dependent on methionine, and MR may inhibit T cell activation, resulting in inability to control tumor growth or resist immunotherapy; while in advanced cancer patients, tumor cells may be more dependent on methionine, and MR can work in conjunction with non-immune-mediated treatment options to inhibit tumor progression. It can be seen that the response to MR treatment is influenced by both immune status and tumor stage, and immunodeficient tumor patients are more sensitive to MR treatment.
Figure 5. . MR has anticancer effects in immunodeficient individuals with tumors that are sensitive to MR. (Ji, M., et. al, 2024)
At present, multiple antitumor drugs targeting the methionine metabolism pathway are in the clinical stage for the highly active methionine metabolism of tumor cells, but there are no relevant clinical trials for cancer treatment that combines MR with immunotherapy. Considering that methionine is an essential amino acid during normal growth and development, and restricting methionine may have adverse consequences, the relative trade-off between adopting MR and expected health outcomes is important, which further demonstrates that targeting the methionine metabolic pathway to achieve relative health benefits must also consider potential physiological, pathological and environmental factors.
Conclusion
With the rapid development of metabolomics and genomics, many important advances have been made in the study of methionine metabolism in recent years. Researchers have revealed the regulatory mechanisms of multiple key enzymes and discovered a close link between methionine metabolism and multiple diseases.
References
- Sanderson, S.M., Gao, X., Dai, Z. et al. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer 19, 625–637 (2019). https://doi.org/10.1038/s41568-019-0187-8
- Haber J. E. (2012). Mating-type genes and MAT switching in Saccharomyces cerevisiae. Genetics, 191(1), 33–64. https://doi.org/10.1534/genetics.111.134577
- Kosakamoto, H., Obata, F., Kuraishi, J., et.al. (2023). Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila. Nature communications, 14(1), 7832. https://doi.org/10.1038/s41467-023-43550-2
- Ji, M., Xu, Q., & Li, X. (2024). Dietary methionine restriction in cancer development and antitumor immunity. Trends in endocrinology and metabolism: TEM, 35(5), 400–412. https://doi.org/10.1016/j.tem.2024.01.009
