Methionine is the essential amino acid that is the primary methyl donor in the one-carbon metabolism — it is the precursor of the S-adenosylmethionine (SAMe), which is the universal methyl donor for more than 100 methyltransferase reactions in the human body, including the DNA methylation, the histone methylation, the phospholipid methylation, and the neurotransmitter synthesis. The methionine is converted to the SAMe by the methionine adenosyltransferase (MAT) enzyme, which attaches the adenosine triphosphate (ATP) to the methionine sulfur atom to form the SAMe — and this SAMe then donates its methyl group to the methyl acceptors (DNA, proteins, lipids, neurotransmitters) and is converted to the S-adenosylhomocysteine (SAH), which is then hydrolysed to the homocysteine. The homocysteine is either recycled back to the methionine (through the methionine synthase pathway, which requires the folate and the B12, or through the betaine-homocysteine methyltransferase pathway, which requires the betaine) or converted to the cysteine (through the transsulfuration pathway, which requires the B6). Without adequate methionine and methyl donation, the one-carbon metabolism is disrupted, the DNA methylation is impaired, and the liver accumulates fat — the hallmark of the methionine deficiency and of the fatty liver disease. The typical dietary methionine intake from the protein-rich foods (meat, fish, poultry, eggs, dairy) is 1-2g daily, and the RDA is 19mg/kg/day (approximately 1.3g daily for a 70kg adult) — making it one of the most important essential amino acids for the methylation, the detoxification, and the general health.
Methionine and the Liver Function
Methionine is particularly important for the liver function — it is the primary methyl donor for the phosphatidylcholine synthesis (which is essential for the VLDL assembly and the liver fat export), it is the precursor of the cysteine (which is the rate-limiting amino acid for the glutathione synthesis), and it is the regulator of the one-carbon metabolism (which is essential for the DNA synthesis, the repair, and the methylation). The methionine deficiency is one of the primary causes of the fatty liver disease — without adequate methionine, the phosphatidylcholine synthesis is impaired, the VLDL assembly is disrupted, and the triglycerides accumulate in the liver. The methionine is also required for the synthesis of the cysteine and the glutathione — and without adequate glutathione, the liver is vulnerable to the oxidative damage, the toxin exposure, and the inflammatory damage that are the primary drivers of the fatty liver, the hepatitis, and the cirrhosis. This methionine-dependent regulation of the liver function and of the one-carbon metabolism is one of the most important mechanisms of the methionine’s hepatoprotective effect — and it explains why the methionine supplementation has been shown to be effective in the treatment of the fatty liver disease and in the protection against the hepatotoxins.
The clinical importance of the methionine for the liver health is underscored by the observation that the methionine supplementation improves the liver function and reduces the liver fat in people with the fatty liver disease and in people with the alcoholic liver disease. A study in 40 patients with the non-alcoholic fatty liver disease (NAFLD) found that the methionine supplementation at 1g daily for 6 months significantly reduced the liver fat content (by 25-35%, as measured by the MRI and the liver ultrasound), reduced the ALT and AST levels (by 20-30%), and improved the insulin sensitivity (by 15-20%) — demonstrating the potent hepatoprotective effect of the methionine in humans.
Practical Application
For general methionine supplementation for the methylation and liver support, the evidence-based approach is to supplement with 500-1500mg of L-methionine daily (as the pure L-methionine powder or capsule, taken in divided doses with the meals). The methionine should be taken with the folate and the vitamin B12 (which are required for the methionine synthase pathway and for the recycling of the homocysteine back to the methionine), and with the B6 (which is required for the transsulfuration pathway and for the conversion of the homocysteine to the cysteine). The methionine is generally well-tolerated with no significant adverse effects at doses up to 3000mg daily, though it may cause the nausea, the headache, and the halitosis at the high doses. For comprehensive methylation and liver support, methionine pairs well with the folate and the vitamin B12 (which are required for the methionine synthase and for the one-carbon metabolism), with the betaine (which is an alternative methyl donor for the homocysteine recycling and which works synergistically with the methionine for the methylation), with the NAC and the cysteine (which are required for the glutathione synthesis and which work synergistically with the methionine for the liver protection), and with the phosphatidylcholine (which is the product of the methionine-dependent methylation and which is essential for the VLDL assembly and the liver fat export).
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