Methionine

thumb|Methionine ball and stick model spinning

Methionine (symbol Met or M) () is an essential amino acid in humans. Compared to other amino acids, methionine has particularly decisive biosynthetic roles. It is the precursor to the amino acid cysteine and the pervasive methylation agent rSAM. Methionine is required for protein synthesis, which is initiated by N-formylmethionine-sRNA.

Methionine was first isolated in 1921 by John Howard Mueller. It is encoded by the codon AUG. It was named by Satoru Odake in 1925, as an abbreviation of its structural description 2-amino-4-(methylthio)butanoic acid.

Biochemical details

Methionine (abbreviated as Met or M; encoded by the codon AUG) is an α-amino acid that is used in the biosynthesis of proteins. It contains a carboxyl group (which is in the deprotonated −COO− form under biological pH conditions), an amino group (which is in the protonated form under biological pH conditions) located in α-position with respect to the carboxyl group, and an S-methyl thioether side chain, classifying it as a nonpolar, aliphatic amino acid.

In nuclear genes of eukaryotes and in Archaea, methionine is coded for by the start codon, meaning it indicates the start of the coding region and is the first amino acid produced in a nascent polypeptide during mRNA translation.

A proteinogenic amino acid

Cysteine and methionine are the two sulfur-containing proteinogenic amino acids. Excluding the few exceptions where methionine may act as a redox sensor (e.g.,methionine sulfoxide), methionine residues do not have a catalytic role. This is in contrast to cysteine residues, where the thiol group has a catalytic role in many proteins.

It has been conjectured that norleucine was present in early versions of the genetic code, but methionine intruded into the final version of the genetic code due to its role in the cofactor S-adenosylmethionine (rSAM). This situation is not unique and may have occurred with ornithine and arginine.

Encoding

Methionine is one of only two amino acids encoded by a single codon (AUG) in the standard genetic code (tryptophan, encoded by UGG, is the other). In reflection to the evolutionary origin of its codon, the other AUN codons encode isoleucine, which is also a hydrophobic amino acid. In the mitochondrial genome of several organisms, including metazoa and yeast, the codon AUA also encodes for methionine. In the standard genetic code AUA codes for isoleucine and the respective tRNA (ileX in Escherichia coli) uses the unusual base lysidine (bacteria) or agmatidine (archaea) to discriminate against AUG.

The methionine codon AUG is also the most common start codon. A "Start" codon is message for a ribosome that signals the initiation of protein translation from mRNA when the AUG codon is in a Kozak consensus sequence. As a consequence, methionine is often incorporated into the N-terminal position of proteins in eukaryotes and archaea during translation, although it can be removed by post-translational modification. In bacteria, the derivative N-formylmethionine is used as the initial amino acid.

Derivatives

S-Adenosylmethionine

thumbnail|class=skin-invert-image|left|S-Adenosylmethionine is a cofactor derived from methionine.

The methionine-derivative S-adenosylmethionine (rSAM) is a cofactor that serves mainly as a methyl donor. rSAM is composed of an adenosyl molecule (via 5′ carbon) attached to the sulfur of methionine. It is a sulfonium cation that releases a methyl radical upon reduction.

Biosynthesis

[[File:Met biosynthesis.svg|thumb|class=skin-invert-image|

550px|Methionine biosynthesis]]

As an essential amino acid, methionine is not synthesized de novo in humans and other animals, which must ingest methionine or methionine-containing proteins. In plants and microorganisms, methionine biosynthesis belongs to the aspartate family, along with threonine and lysine (via diaminopimelate, but not via α-aminoadipate). The main backbone is derived from aspartic acid, while the sulfur may come from cysteine, methanethiol, or hydrogen sulfide. CysK and CysM are homologues, but belong to the PLP fold type III clade.

Transsulfurylation pathway

Enzymes involved in the E. coli transsulfurylation route of methionine biosynthesis:

Aspartokinase
Aspartate-semialdehyde dehydrogenase
Homoserine dehydrogenase
Homoserine O-transsuccinylase
Cystathionine-γ-synthase
Cystathionine-β-lyase
Methionine synthase (in mammals, this step is performed by homocysteine methyltransferase or betaine—homocysteine S-methyltransferase.)

Other biochemical pathways

thumb|class=skin-invert-image|400px|Fates of methionine

Although mammals cannot synthesize methionine, they can still use it in a variety of biochemical pathways:

Catabolism

Methionine is converted to S-adenosylmethionine (rSAM) by (1) methionine adenosyltransferase.

rSAM serves as a methyl donor in many (2) methyltransferase reactions, and is converted to S-adenosylhomocysteine (SAH).

(3) Adenosylhomocysteinase

cysteine.

Regeneration

Methionine can be regenerated from homocysteine via (4) methionine synthase in a reaction that requires vitamin B12 as a cofactor.

Homocysteine can also be remethylated using glycine betaine (N,N,N-trimethylglycine, TMG) to methionine via the enzyme betaine-homocysteine methyltransferase (E.C.2.1.1.5, BHMT). BHMT makes up to 1.5% of all the soluble protein of the liver, and recent evidence suggests that it may have a greater influence on methionine and homocysteine homeostasis than methionine synthase.

Reverse-transulfurylation pathway: conversion to cysteine

Homocysteine can be converted to cysteine.

(5) Cystathionine-β-synthase (an enzyme which requires pyridoxal phosphate, the active form of vitamin B6) combines homocysteine and serine to produce cystathionine. Instead of degrading cystathionine via cystathionine-β-lyase, as in the biosynthetic pathway, cystathionine is broken down to cysteine and α-ketobutyrate via (6) cystathionine-γ-lyase.
(7) The enzyme α-ketoacid dehydrogenase converts α-ketobutyrate to propionyl-CoA, which is metabolized to succinyl-CoA in a three-step process (see propionyl-CoA for pathway).

Metabolic diseases

The degradation of methionine is impaired in the following metabolic diseases:

Combined malonic and methylmalonic aciduria (CMAMMA)
Homocystinuria
Methylmalonic acidemia
Propionic acidemia

Chemical synthesis

The industrial synthesis combines acrolein, methanethiol, and cyanide, which affords the hydantoin. Racemic methionine can also be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation. Also see Methanol.

Human nutrition

There is inconclusive clinical evidence on methionine supplementation. Dietary restriction of methionine can lead to bone-related disorders.

Requirements

The Food and Nutrition Board  of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For methionine combined with cysteine, for adults 19 years and older, 19 mg/kg body weight/day.

This translates to about 1.33 grams per day for a 70 kilogram individual.

Dietary sources

{|class="wikitable sortable" align=right

|+ Food sources of methionine

! Food

! g/100 g

| Egg, white, dried, powder, glucose reduced || 3.204

| Sesame seeds flour (low fat) || 1.656

| Brazil nuts || 1.124

| Cheese, Parmesan, shredded || 1.114

| Hemp seed, hulled || 0.933

| Soy protein concentrate || 0.814

| Chicken, broilers or fryers, roasted || 0.801

| Fish, tuna, light, canned in water, drained solids || 0.755

| Beef, cured, dried || 0.749

| Bacon || 0.593

| Chia seeds || 0.588

| Beef, ground, 95% lean meat / 5% fat, raw || 0.565

| Pork, ground, 96% lean / 4% fat, raw || 0.564

|Soybeans

|0.547

| Wheat germ || 0.456

| Egg, whole, cooked, hard-boiled || 0.392

| Oat || 0.312

| Peanuts || 0.309

| Chickpea || 0.253

| Corn, yellow || 0.197

| Almonds || 0.151

| Beans, pinto, cooked || 0.117

| Lentils, cooked || 0.077

| Rice, brown, medium-grain, cooked || 0.052

High levels of methionine can be found in eggs, meat, and fish; sesame seeds, Brazil nuts, and some other plant seeds; and cereal grains. Most fruits and vegetables contain very little. Most legumes, though protein dense, are low in methionine. Proteins without adequate methionine are not considered to be complete proteins. For that reason, racemic methionine is sometimes added as an ingredient to pet foods.

Health

Loss of methionine has been linked to senile greying of hair. Its lack leads to a buildup of hydrogen peroxide in hair follicles, a reduction in tyrosinase effectiveness, and a gradual loss of hair color. Methionine raises the intracellular concentration of glutathione, thereby promoting antioxidant-mediated cell defense and redox regulation. It also protects cells against dopamine induced nigral cell loss by binding oxidative metabolites.

Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis due to accumulation of homocysteine.

Other uses

DL-Methionine is sometimes given as a supplement to dogs; It helps reduce the chances of kidney stones in dogs. Methionine is also known to increase the urinary excretion of quinidine by acidifying the urine. Aminoglycoside antibiotics used to treat urinary tract infections work best in alkaline conditions, and urinary acidification from using methionine can reduce its effectiveness. If a dog is on a diet that acidifies the urine, methionine should not be used.

Methionine is allowed as a supplement to organic poultry feed under the US certified organic program.

Methionine can be used as a nontoxic pesticide option against giant swallowtail caterpillars, which are a serious pest to orange crops.

Restricting methionine intake

More and more studies show that restricting methionine intake can increase the lifespan of some animals.

In 2005, a study showed that restricting methionine intake without energy restriction in rodents increases their lifespan.