Methionine

Methionine
IUPAC name Methionine
Other names 2-amino-4-(methylthio)butanoic acid
Identifiers
Abbreviations	Met, M
CAS number	59-51-8 Y, 63-68-3 (L-isomer) Y, 348-67-4 (D-isomer) Y
PubChem	876
ChemSpider	853 Y, 5907 (L-isomer)
UNII	73JWT2K6T3 Y
EC-number	200-432-1
KEGG	D04983 Y
ChEBI	CHEBI:16811 Y
ChEMBL	CHEMBL42336 N
ATC code	V03AB26,QA05BA90, QG04BA90
Jmol-3D images	Image 1 Image 2
SMILES CSCCC(C(=O)O)N CSCCC(C(=O)O)N
InChI InChI=1S/C5H11NO2S/c1-9-3-2-4(6)5(7)8/h4H,2-3,6H2,1H3,(H,7,8) Y Key: FFEARJCKVFRZRR-UHFFFAOYSA-N Y InChI=1/C5H11NO2S/c1-9-3-2-4(6)5(7)8/h4H,2-3,6H2,1H3,(H,7,8)
Properties[1]
Molecular formula	C5H11NO2S
Molar mass	149.21 g mol−1
Appearance	White crystalline powder
Density	1.340 g/cm3
Melting point	281 °C decomp.
Solubility in water	Soluble
Acidity (pKa)	2.28 (carboxyl), 9.21 (amino)[2]
Supplementary data page
Structure and properties	n, εr, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Methionine (/mɛˈθaɪ.ɵniːn/ or /mɛˈθaɪ.ɵnɪn/; abbreviated as Met or M)^[3] is an α-amino acid with the chemical formula HO₂CCH(NH₂)CH₂CH₂SCH₃. This essential amino acid is classified as nonpolar. This amino-acid is coded by the initiation codon AUG which indicates mRNA's coding region where translation into protein begins.

Function

Together with cysteine, methionine is one of two sulfur-containing proteinogenic amino acids. Its derivative S-adenosyl methionine (SAM) serves as a methyl donor. Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis.^[4]

This amino acid is also used by plants for synthesis of ethylene. The process is known as the Yang Cycle or the methionine cycle.

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). The codon AUG is also the most common eukaryote "Start" 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.

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. ^[5]

Zwitterions

Biosynthesis

As an essential amino acid, methionine is not synthesized de novo in humans, who must ingest methionine or methionine-containing proteins. In plants and microorganisms, methionine is synthesized via a pathway that uses both aspartic acid and cysteine. First, aspartic acid is converted via β-aspartyl-semialdehyde into homoserine, introducing the pair of contiguous methylene groups. Homoserine converts to O-succinyl homoserine, which then reacts with cysteine to produce cystathionine, which is cleaved to yield homocysteine. Subsequent methylation of the thiol group by folates affords methionine. Both cystathionine-γ-synthase and cystathionine-β-lyase require pyridoxyl-5'-phosphate as a cofactor, whereas homocysteine methyltransferase requires vitamin B₁₂ as a cofactor.^[6]

Enzymes involved in methionine biosynthesis:

1. Aspartokinase
2. Aspartate-semialdehyde_dehydrogenase
3. Homoserine dehydrogenase
4. Homoserine O-transsuccinylase
5. Cystathionine-γ-synthase
6. Cystathionine-β-lyase
7. Methionine synthase (in mammals, this step is performed by Homocysteine methyltransferase or Betaine—homocysteine S-methyltransferase)

Methionine biosynthesis

Other biochemical pathways

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

Generation of homocysteine

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

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

(3) Adenosylhomocysteinase converts SAH to homocysteine.

There are two fates of homocysteine: it can be used to regenerate methionine, or to form cysteine.

Regeneration of methionine

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 (NNN-trimethyl glycine, 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.

Conversion to cysteine

Homocysteine can be converted to cysteine.

• (5) Cystathionine-β-synthase (a PLP-dependent enzyme) 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).

Synthesis

Racemic methionine can be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH₂CH₂SCH₃) followed by hydrolysis and decarboxylation.^[7]

Dietary sources

Food sources of Methionine^[8]

Food	g/100g
Egg, white, dried, powder, glucose reduced	3.204
Sesame seeds flour (low fat)	1.656
Egg, whole, dried	1.477
Cheese, Parmesan, shredded	1.114
Brazil nuts	1.008
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
Beef, ground, 95% lean meat / 5% fat, raw	0.565
Pork, ground, 96% lean / 4% fat, raw	0.564
Wheat germ	0.456
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, sesame seeds, Brazil nuts, fish, meats and some other plant seeds; methionine is also found in cereal grains. Most fruits and vegetables contain very little of it. Most legumes are also low in methionine. Racemic methionine is sometimes added as an ingredient to pet foods.^[9]

Methionine restriction

There is scientific evidence that restricting methionine consumption can increase lifespans in some animals.^[10]

A 2005 study showed methionine restriction without energy restriction extends mouse lifespan.^[11]

A study published in Nature showed adding just the essential amino acid methionine to the diet of fruit flies under dietary restriction, including restriction of essential amino acids (EAAs), restored fertility without reducing the longer lifespans that are typical of dietary restriction, leading the researchers to determine that methionine “acts in combination with one or more other EAAs to shorten lifespan.”^[12][13]

Several studies showed that methionine restriction also inhibits aging-related disease processes in mice^[14][15] and inhibits colon carcinogenesis in rats.^[16]

A 2009 study on rats showed "methionine supplementation in the diet specifically increases mitochondrial ROS production and mitochondrial DNA oxidative damage in rat liver mitochondria offering a plausible mechanism for its hepatotoxicity".^[17]

However, since methionine is an essential amino acid, it should not be entirely removed from animals' diets without disease or death occurring over time. For example, rats fed a diet without methionine developed steatohepatitis (fatty liver), anemia and lost two thirds of their body weight over 5 weeks. Administration of methionine ameliorated the pathological consequences of methionine deprivation.^[18]

Other uses

DL-Methionine is sometimes given as a supplement to dogs; it helps keep dogs from damaging grass by reducing the pH of the urine.^[19]

Methionine is allowed as a supplement to organic poultry feed under the US certified organic program.^[20]

See also

• Allantoin
• Formylmethionine
• Methionine oxidation
• Paracetamol poisoning - A Methionine-Paracetamol preparation that might prevent hepatotoxicity.
• Photo-reactive methionine

References

External links

• Rudra, M. N.; Chowdhury, L. M. (30 September 1950). "Methionine Content of Cereals and Legumes". Nature 166 (568): 568. Bibcode:1950Natur.166..568R. doi:10.1038/166568a0 
• Food Sources of Methionine
• Foods containing methionine

v t e The 20 common amino acids General topics Protein Peptide Genetic code By properties Aliphatic Branched-chain amino acids (Valine Isoleucine Leucine) Methionine Alanine Proline Glycine Aromatic Phenylalanine Tyrosine Tryptophan Histidine Polar, uncharged Asparagine Glutamine Serine Threonine Positive charge (pKa) Lysine (≈10.8) Arginine (≈12.5) Histidine (≈6.1) Negative charge (pKa) Aspartic acid (≈3.9) Glutamic acid (≈4.1) Cysteine (≈8.3) Tyrosine (≈10.1) Other classifications Essential amino acid Ketogenic amino acid Glucogenic amino acid Non-proteinogenic amino acid Biochemical families: carbohydrates alcohols glycoproteins glycosides lipids eicosanoids fatty acids / intermediates phospholipids sphingolipids steroids nucleic acids constituents / intermediates proteins Amino acids / intermediates tetrapyrroles / intermediates

v t e Antidotes (V03AB) Nervous system Nerve agent / Organophosphate poisoning Atropine# Biperiden Diazepam# Oximes Obidoxime Pralidoxime see also: Cholinesterase Barbiturate overdose Bemegride Ethamivan Benzodiazepine overdose Cyprodenate Flumazenil GHB overdose Physostigmine SCH-50911 Opioid overdose Diprenorphine Doxapram Nalmefene Nalorphine Naloxone# Naltrexone Reversal of neuromuscular blockade Sugammadex Circulatory system Beta blocker Glucagon Digoxin toxicity Digoxin Immune Fab Heparin Protamine# Other Arsenic poisoning Dimercaprol# Succimer Cyanide poisoning 4-Dimethylaminophenol Hydroxocobalamin nitrite Amyl nitrite Sodium nitrite# Sodium thiosulfate# Hydrofluoric acid Calcium gluconate# Methanol / Ethylene glycol poisoning Ethanol Fomepizole Paracetamol toxicity (Acetaminophen) Acetylcysteine# Glutathione Methionine# Toxic metals (cadmium lead mercury thallium) Dimercaprol# Edetates Prussian blue# Other iodine-131 Potassium iodide Methylthioninium chloride# oxidizing agent Potassium permanganate Prednisolone/promethazine Emetic Copper sulfate Ipecacuanha Syrup of ipecac #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III M: TOX gen / txn pto ant

v t e Amino acid metabolism metabolic intermediates K→acetyl-CoA lysine→ Saccharopine Allysine α-Aminoadipic acid α-Aminoadipate Glutaryl-CoA Glutaconyl-CoA Crotonyl-CoA β-Hydroxybutyryl-CoA leucine→ α-Ketoisocaproic acid Isovaleryl-CoA 3-Methylcrotonyl-CoA 3-Methylglutaconyl-CoA HMG-CoA tryptophan→alanine→ N'-Formylkynurenine Kynurenine Anthranilic acid 3-Hydroxykynurenine 3-Hydroxyanthranilic acid 2-Amino-3-carboxymuconic semialdehyde 2-Aminomuconic semialdehyde 2-Aminomuconic acid Glutaryl-CoA G G→pyruvate→citrate glycine→serine→ 3-Phosphoglyceric acid glycine→creatine: Glycocyamine Phosphocreatine Creatinine G→glutamate→ α-ketoglutarate histidine→ Urocanic acid Imidazol-4-one-5-propionic acid Formiminoglutamic acid Glutamate-1-semialdehyde proline→ 1-Pyrroline-5-carboxylic acid arginine→ Ornithine Putrescine Agmatine other cysteine+glutamate→glutathione: γ-Glutamylcysteine G→propionyl-CoA→ succinyl-CoA valine→ α-Ketoisovaleric acid Isobutyryl-CoA Methacrylyl-CoA 3-Hydroxyisobutyryl-CoA 3-Hydroxyisobutyric acid 2-Methyl-3-oxopropanoic acid isoleucine→ 2,3-Dihydroxy-3-methylpentanoic acid 2-Methylbutyryl-CoA Tiglyl-CoA 2-Methylacetoacetyl-CoA methionine→ generation of homocysteine: S-Adenosyl methionine S-Adenosyl-L-homocysteine Homocysteine conversion to cysteine: Cystathionine alpha-Ketobutyric acid+Cysteine threonine→ α-Ketobutyric acid propionyl-CoA→ Methylmalonyl-CoA G→fumarate phenylalanine→tyrosine→ 4-Hydroxyphenylpyruvic acid Homogentisic acid 4-Maleylacetoacetate G→oxaloacetate see urea cycle Other Cysteine metabolism Cysteine sulfinic acid M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m) Biochemical families: carbohydrates alcohols glycoproteins glycosides lipids eicosanoids fatty acids / intermediates phospholipids sphingolipids steroids nucleic acids constituents / intermediates proteins Amino acids / intermediates tetrapyrroles / intermediates