What is methionine

Methionine (C5-H11-N-O2-S) is one of nine essential amino acids in humans that needs to be provided by food. Methionine is often the most limiting amino acid in the diets of the developing world’s population because of its low concentration in cereal grains ¹. Methionine is required for normal growth, tissue repair and development of humans ². A sulphur-containing amino acid, methionine improves the tone and pliability of skin, hair, and strengthens nails. Burn patients may have an increased demand for methionine to maintain nitrogen balance ³. Methionine is involved in many detoxifying processes, sulphur provided by methionine protects cells from pollutants, slows cells aging, and is essential for absorption and bio-availability of selenium and zinc. Methionine chelates heavy metals, such as lead and mercury, aiding their excretion. Methionine is also acts as a lipotropic agent and prevents excess fat buildup in the liver.

There is a general consensus concerning normal sulfur amino acid requirements. From the classical experiments of Rose ⁴ in healthy men, it was calculated that the minimal intake of methionine required to maintain nitrogen balance is 1.10 g/day, which comes down to ∼13 mg/kg body weight per day. The World Health Organization (WHO) recommendations amount to 13 mg/kg per 24 hour in healthy adults. This amount is roughly doubled in artificial nutrition regimens. In a recent study it was shown that this intake also is sufficient to maintain glutathione synthesis in healthy volunteers ⁵. In infancy and childhood, the dietary requirement for sulfur amino acid is higher ⁶. Sulfur amino acid requirements in elderly subjects are unknown, but it has been suggested that the altered redox state reported in the elderly ⁷ requires increased ingestion of sulfur amino acid. In contrast, the safe upper limit of chronic sulfur amino acid supplementation may be reached earlier in the elderly because of accumulation of homocysteine, which is considered a risk factor for the development of atherosclerosis ⁸. Hyperhomocysteinemia may, however, be prevented by adequate vitamin B and folate supplementation.

In disease or after trauma, requirements may be altered for methionine, cysteine, and taurine. Although in specific cases of congenital enzyme deficiency, prematurity, or diminished liver function, hypermethioninemia or hyperhomocysteinemia may occur, sulfur amino acid supplementation can be considered safe in amounts exceeding 2-3 times the minimum recommended daily intake. Apart from some very specific indications (e. g. acetaminophen poisoning) the usefulness of sulfur amino acid supplementation is not yet established ⁶.

Methionine is the only essential sulfur amino acid and can provide sulfur for cysteine and taurine synthesis. Animal protein is generally considered to be a better source of sulfur amino acid than vegetable protein ⁶. This is primarily because the biological value of animal protein is higher than that of vegetable protein ⁹. Soy, which is the only vegetable protein used for artificial enteral nutrition, is also low in absolute sulfur amino acid content ⁹.

The sulfur amino acid, methionine, has gained renewed interest in recent years largely because of its relation to homocysteine and glutathione (Figure 1). Methionine breakdown occurs by transmethylation to homocysteine ¹⁰. The first step in this pathway is the conversion of methionine to S-adenosylmethionine, which can donate its methyl group for numerous methylation processes including DNA methylation. Separation of the methyl group yields S-adenosylhomocysteine, which can be converted to homocysteine. Homocysteine can be remethylated to methionine by the folate (vitamin B9) and vitamin B-12-dependent enzyme methionine synthetase or enter the irreversible transsulfuration pathway. Homocysteine is a central product in the metabolic pathway of methionine metabolism, and hyperhomocysteinemia has been identified as an independent risk factor for cardiovascular disease in adults ¹¹, ischemic and hemorrhagic stroke in newborns and children ¹² and Alzheimer’s disease in adults ¹³. A high plasma total homocysteine concentration is a risk factor for cardiovascular disease ¹⁴. However despite the function of methionine as a precursor of homocysteine, and the role of homocysteine in vascular damage and cardiovascular disease, there is no evidence that dietary intake of methionine within reasonable limits will cause cardiovascular damage ¹⁵. But intakes higher than 5 times normal (1.10 g/day or 13 mg/kg body weight per day) resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, vitamin B-12, vitamin C, and folic acid ¹⁵.

The increase in total homocysteine induced by methionine, the sole dietary precursor of homocysteine, might be modulated by other amino acids present in dietary proteins. A randomized crossover trial was conducted in 24 healthy men. Each subject ingested 4 meals on separate days, which were separated by 1 week. Total homocysteine concentrations were measured in the fasting state and at 2, 4, 6, 8, 10, and 24 hours after meal ingestion. The meals were #1) a low-protein meal fortified with 30 mg methionine/kg body body weight (methionine only); #2) meal 1 additionally fortified with 60.6 mg serine/kg body body weight (Methionine + Serine); #3) meal 1 additionally fortified with 12.3 mg cystine/kg body body weight (Methionine + Cystine) and 4) a protein-rich meal containing 30 mg methionine, 60.6 mg serine, and 12.3 mg cystine per kg body body weight (Methionine + Serine + Cystine). RESULTS: The mean fasting total homocysteine concentration was 37% (Methionine + Serine), 32% (Methionine + Cystine) and 77%  (Methionine + Serine + Cystine) lower. CONCLUSIONS: Dietary methionine increases total homocysteine much less than does free methionine. Serine and cystine reduce the total homocysteine-raising effect of free methionine (i.e. methionine supplement). Thus, dietary proteins with a high content of serine or cystine relative to methionine may lead to lower postprandial total homocysteine responses ¹⁴.

Methionine is also required for synthesis of cysteine. Undisputed functions of cysteine include protein synthesis and the biosynthesis of taurine, sulfate ¹⁶ and glutathione ¹⁷. However, the ability of cysteine to provide a portion of the total sulfur amino acid requirement in humans, thereby providing a sparing effect on the dietary methionine requirement, has been an area of considerable debate.

Methionine is accepted as the metabolic precursor for cysteine ¹⁸. Only the sulfur atom from methionine is transferred to cysteine; the carbon skeleton of cysteine is donated by serine ¹⁸. Cysteine is not a precursor for methionine because of the irreversibility of the cystathionase synthase reaction ¹⁹ (see Figure 1). Consequently, any substitution by cysteine for dietary methionine requirement can only be via inhibition of the sulfur amino acid pathway that leads to synthesis of the transsulfuration metabolites, including cysteine itself.

Glutathione, the most prevalent intracellular thiol ²⁰ and an important endogenous antioxidant and scavenger ²¹, is synthesized de novo within all cells ²², and intracellular availability of cysteine is believed to be the most important rate-limiting factor for glutathione synthesis ¹⁷. More importantly, glutathione concentrations are reduced in several disease states including HIV ²³, liver cirrhosis ²⁴, diabetes ²⁵ and Alzheimer’s disease ²⁶. Glutathione concentration is also found to be reduced in surgical trauma patients ²⁷, septic patients ²⁸, premature infants ²⁹, and in children with severe protein–energy malnutrition ³⁰. Comprehensive understanding of sulfur amino acid requirements and their complex metabolism clearly has many implications for human health.

When present in sufficiently high levels, methionine can act as an atherogen and a metabotoxin. An atherogen is a compound that when present at chronically high levels causes atherosclerosis and cardiovascular disease ¹⁵. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of methionine are associated with at least ten inborn errors of metabolism, including cystathionine beta-synthase deficiency, glycine N-methyltransferase deficiency, homocystinuria, tyrosinemia, galactosemia, homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, methionine adenosyltransferase deficiency, methylenetetrahydrofolate reductase deficiency, and S-adenosylhomocysteine hydrolase deficiency. Chronically elevated levels of methionine in infants can lead to intellectual disability and other neurological problems, delays in motor skills, sluggishness, muscle weakness, and liver problems ¹⁵. Many individuals with these metabolic disorders tend to develop cardiovascular disease later in life. Studies on feeding rodents high levels of methionine have shown that methionine promotes atherosclerotic plaques independently of homocysteine levels ³¹. A similar study in Finnish men showed the same effect where it was found that “long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior coronary heart disease”³².

Figure 1. Methionine metabolism in mammalian tissue

Footnotes: Illustration of the pathways of methionine metabolism in mammalian tissue via transmethylation (TM), transsfulfuration (TS), and remethylation (RM). The numbers represent the following enzymes or reaction sequences: 1, L-methionine-S-adenosyl-transferase; 2, transmethylation reaction; 3, adenosylhomocysteinease; 4, cystathionine-β-synthase; 5, cystathionase; 6, multiple reactions leading from methionine to sulfate or taurine, cysteine used for protein or GSH or protein synthesis, or the reversible conversion between cysteine and cystine; 7, betaine-homocysteine methyl transferase; 8, methyltetrahydrofolate homocysteine methyltransferase; 9, choline dehydrogenase and betaine aldehyde dehydrogenase; 10, serine hydroxymethylase; 11, methylene tetrehydrofolate reductase.

[Source ¹]

In addition to being a substrate for protein synthesis, mehionine is an intermediate in transmethylation reactions, serving as the major methyl group donor in vivo, including the methyl groups for DNA and RNA intermediates. Methionine is a methyl acceptor for 5-methyltetrahydrofolate-homocysteine methyltransferase (methionine synthase), the only reaction that allows for the recycling of this form of folate, and is also a methyl acceptor for the catabolism of betaine. Methionine is the metabolic precursor for cysteine. Only the sulfur atom from methionine is transferred to cysteine; the carbon skeleton of cysteine is donated by serine ¹.

Methionine is known to exacerbate psychopathological symptoms in schizophrenic patients, but there is no evidence of similar effects in healthy subjects. The role of methionine as a precursor of homocysteine is the most notable cause for concern. Acute doses of methionine can lead to acute increases in plasma homocysteine, which can be used as an index of the susceptibility to cardiovascular disease. Sufficiently high doses of methionine can actually result in death. Longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times the normal amount resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, B-12, C, and folic acid ¹⁵.

Methionine rich foods

Table 1. Foods high in methionine (ordered from highest to low)

Description	Methionine (g) Value Per 100 gram
Egg, white, dried, powder, stabilized, glucose reduced	3.2
Egg, white, dried, flakes, stabilized, glucose reduced	2.99
Egg, white, dried, stabilized, glucose reduced	2.99
Egg, white, dried	2.79
Fish, cod, Atlantic, dried and salted	1.86
Seeds, sesame flour, low-fat	1.66
Egg, whole, dried, stabilized, glucose reduced	1.56
Egg, whole, dried	1.5
Whale, beluga, meat, dried (Alaska Native)	1.35
Seeds, sesame flour, partially defatted	1.33
Mollusks, whelk, unspecified, cooked, moist heat	1.21
Seaweed, spirulina, dried	1.15
Beef, New Zealand, imported, brisket point end, separable lean only, cooked, braised	1.14
Soy protein isolate	1.13
Soy protein isolate, potassium type	1.13
Nuts, brazilnuts, dried, unblanched	1.12
Cheese, parmesan, shredded	1.11
Beef, New Zealand, imported, bolar blade, separable lean only, cooked, fast roasted	1.1
Beef, New Zealand, imported, flat, separable lean only, cooked, braised	1.09
Lamb, New Zealand, imported, fore-shank, separable lean only, cooked, braised	1.09
Pork, cured, bacon, cooked, microwaved	1.07
Lamb, New Zealand, imported, hind-shank, separable lean only, cooked, braised	1.06
Beef, New Zealand, imported, chuck eye roll, separable lean only, raw	1.05
Beef, New Zealand, imported, chuck eye roll, separable lean only, cooked, braised	1.05
Beef, New Zealand, imported, brisket point end, separable lean and fat, cooked, braised	1.05
Beef, New Zealand, imported, flat, separable lean and fat, cooked, braised	1.05
Seeds, sunflower seed flour, partially defatted	1.04
Beef, New Zealand, imported, variety meats and by-products, heart, cooked, boiled	1.03
Beef, New Zealand, imported, bolar blade, separable lean and fat, cooked, fast roasted	1.03
Beef, New Zealand, imported, hind shin, separable lean only, cooked, braised	1.03
Lamb, New Zealand, imported, neck chops, separable lean only, cooked, braised	1.02
Seeds, sesame flour, high-fat	1.02
Lamb, New Zealand, imported, square-cut shoulder chops, separable lean only, cooked, braised	1.01
Beef, New Zealand, imported, flank, separable lean only, cooked, braised	1.01
Beef, New Zealand, imported, rump centre, separable lean only, cooked, fast fried	0.99
Beef, New Zealand, imported, flank, separable lean and fat, cooked, braised	0.99
Lamb, New Zealand, imported, fore-shank, separable lean and fat, cooked, braised	0.99
Beef, New Zealand, imported, cube roll, separable lean only, cooked, fast roasted	0.99
Beef, round, top round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.99
Beef, New Zealand, imported, rump centre, separable lean and fat, cooked, fast fried	0.99
Beef, New Zealand, imported, chuck eye roll, separable lean and fat, raw	0.98
Beef, New Zealand, imported, chuck eye roll, separable lean and fat, cooked, braised	0.98
Beef, New Zealand, imported, oyster blade, separable lean only, cooked, braised	0.98
Beef, round, eye of round roast, boneless, separable lean only, trimmed to 0″ fat, select, cooked, roasted	0.98
Beef, New Zealand, imported, hind shin, separable lean and fat, cooked, braised	0.98
Beef, New Zealand, imported, oyster blade, separable lean and fat, cooked, braised	0.98
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, choice, cooked, braised	0.98
Beef, New Zealand, imported, eye round, separable lean only, cooked, slow roasted	0.98
Beef, loin, top sirloin filet, boneless, separable lean only, trimmed to 0″ fat, select, cooked, grilled	0.97
Beef, chuck, mock tender steak, boneless, separable lean only, trimmed to 0″ fat, all grades, cooked, braised	0.97

[Source ³³]

Methionine supplement side effects

When present in sufficiently high levels, methionine can act as an atherogen and a metabotoxin. An atherogen is a compound that when present at chronically high levels causes atherosclerosis and cardiovascular disease ¹⁵. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of methionine are associated with at least ten inborn errors of metabolism, including cystathionine beta-synthase deficiency, glycine N-methyltransferase deficiency, homocystinuria, tyrosinemia, galactosemia, homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, methionine adenosyltransferase deficiency, methylenetetrahydrofolate reductase deficiency, and S-adenosylhomocysteine hydrolase deficiency. Chronically elevated levels of methionine in infants can lead to intellectual disability and other neurological problems, delays in motor skills, sluggishness, muscle weakness, and liver problems ¹⁵. Many individuals with these metabolic disorders tend to develop cardiovascular disease later in life. Studies on feeding rodents high levels of methionine have shown that methionine promotes atherosclerotic plaques independently of homocysteine levels ³¹. A similar study in Finnish men showed the same effect where it was found that “long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior coronary heart disease”³².

Methionine has gained renewed interest in recent years largely because of their relation to homocysteine and glutathione (see Figure 1). Homocysteine is a central product in the metabolic pathway of methionine metabolism, and hyperhomocysteinemia has been identified as an independent risk factor for cardiovascular disease in adults ¹¹, ischemic and hemorrhagic stroke in newborns and children ¹² and Alzheimer’s disease in adults ¹³. Glutathione, the most prevalent intracellular thiol ²⁰ and an important endogenous antioxidant and scavenger ²¹, is synthesized de novo within all cells ²², and intracellular availability of cysteine is believed to be the most important rate-limiting factor for glutathione synthesis ¹⁷. More importantly, glutathione concentrations are reduced in several disease states including HIV ²³, liver cirrhosis ²⁴, diabetes ²⁵ and Alzheimer’s disease ²⁶. Glutathione concentration is also found to be reduced in surgical trauma patients ²⁷, septic patients ²⁸, premature infants ²⁹, and in children with severe protein–energy malnutrition ³⁰. Comprehensive understanding of sulfur amino acid requirements and their complex metabolism clearly has many implications for human health.

Toxicity of methionine in liver disease was established halfway through the twentieth century by Dame Sheila Sherlock ³⁴, who recognized that high methionine intake (∼10 g per day or 133 mg/kg per day for a 75 kg person) in patients with impaired liver function resulted in hyperammonemia and a deterioration of neurological functions, which could be alleviated with antibiotics. In addition, high levels of methionine may be directly hepatotoxic, and it has been suggested from results of animal studies that high amounts of methionine in feeding formulas are causally related to the onset of cholestasis during tube feeding or parenteral feeding ³⁵. It has been shown that there is no relation between methionine intake and hyperhomocysteinemia, provided that vitamin status is optimal. In most cases hyperhomocysteinemia can be treated by vitamin B-12 (Cobalamin), vitamin B-6 (Pyridoxine), and/or folate (vitamin B-9) supplementation ³⁶. In the old literature it is mentioned that methionine restriction and cysteine supplementation can prevent cognitive retardation in children with inborn errors of sulfur amino acid metabolism ³⁷.

Oral methionine supplements (8.0 g daily for 4 days) were given to five normal volunteers who continued to eat their usual diet ³⁸. This treatment resulted in a significant fall in serum folate (vitamin B-9) concentration. Three days after the end of treatment concentrations had not completely returned to control values. The fall in concentration was prevented by giving oral folic acid supplements. The study authors suggested that folic acid supplements should be given to patients who are receiving intravenous infusions of methionine amino acid mixtures.

As an essential amino acid, methionine is a standard component of artificial feeding formulas. According to the reported methionine amount and dose recommendation of standard tube feeds (Table 2), the daily amount of methionine administered to enterally or parenterally fed patients is ∼26 mg/kg per day, which apparently is twice the minimally required amount. Disease-specific feeds for malnutrition or metabolic stress are even higher in total protein and sulfur amino acid content and provide ∼4 times the recommended daily dose of sulfur amino acid ⁶.

Table 2. Sulfur amino acid content of commercially available feeding solutions

[Source ⁶]

Amino acid concentrations of pediatric protein and hydrolysate-based enteral formulas exceed that of breast milk, leading to a moderate increase of plasma levels of amino acids and urea nitrogen in enterally fed children ³⁹. The consequences of this mild elevation of blood nitrogen concentration are difficult to assess in the light of the other differences between formula feeds and mother milk. However, no clinical data indicating specific amino acid toxicity in formula-fed children without errors in metabolism are known.

Methionine intake in infants at 14–28 days with various formulas may reach up to 120 mg/kg per day ⁴⁰. A methionine-fortified hydrolysate providing up to 260 mg/kg per day to newborn healthy children was shown to induce only moderate elevations in methionine plasma level and no signs of methionine toxicity ⁴¹. In a retrospective case study of 10 children without enzyme deficiencies receiving the same methionine-fortified formula, however, severe hypermethionemia was found, which may have induced brain edema in 2 patients ⁴⁰. A conclusive explanation for the increased sensitivity to high methionine intake was not given, but these findings led the authors to suggest that precaution is especially warranted in premature children, children with a very low birth weight, and children with liver disease.

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