Methionine

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Methionine
Chemical structure of methionine
Skeletal formula of the canonical form of methionine
Names
IUPAC name
Methionine
Other names
2-amino-4-(methylthio)butanoic acid
Identifiers
3D model (
JSmol
)
Abbreviations Met, M
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
100.000.393 Edit this at Wikidata
EC Number
  • L: 200-432-1
KEGG
UNII
  • InChI=1S/C5H11NO2S/c1-9-3-2-4(6)5(7)8/h4H,2-3,6H2,1H3,(H,7,8)/t4-/m0/s1 checkY
    Key: FFEARJCKVFRZRR-BYPYZUCNSA-N checkY
  • D/L: Key: FFEARJCKVFRZRR-UHFFFAOYSA-N
  • D: Key: FFEARJCKVFRZRR-SCSAIBSYSA-N
  • L: CSCC[C@H](N)C(=O)O
  • L Zwitterion: CSCC[C@H]([NH3+])C(=O)[O-]
Properties[2]
C5H11NO2S
Molar mass 149.21 g·mol−1
Appearance White crystalline powder
Density 1.340 g/cm3
Melting point 281 °C (538 °F; 554 K) decomposes
Soluble
Acidity (pKa) 2.28 (carboxyl), 9.21 (amino)[1]
Pharmacology
V03AB26 (WHO) QA05BA90 (WHO), QG04BA90 (WHO)
Supplementary data page
Methionine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Methionine (symbol Met or M)[3] (/mɪˈθənn/)[4] is an essential amino acid in humans.

As the precursor of other non-essential amino acids such as

SAM-e, and the important antioxidant glutathione, methionine plays a critical role in the metabolism and health of many species, including humans. Methionine is also involved in angiogenesis
and various processes related to DNA transcription, epigenetic expression, and gene regulation.

Methionine was first isolated in 1921 by

codon AUG. It was named by Satoru Odake in 1925, as an abbreviation of its structural description 2-amino-4-(methylthio)butanoic acid.[6]

Biochemical details

Methionine (abbreviated as Met or M; encoded by the codon AUG) is an α-

thioether side chain, classifying it as a nonpolar, aliphatic
amino acid.

In nuclear genes of

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[8]), methionine residues do not have a catalytic role.[9] This is in contrast to cysteine residues, where the thiol group has a catalytic role in many proteins.[9] The thioether within methionine does however have a minor structural role due to the stability effect of S/π interactions between the side chain sulfur atom and aromatic amino acids in one-third of all known protein structures.[9] This lack of a strong role is reflected in experiments where little effect is seen in proteins where methionine is replaced by norleucine, a straight hydrocarbon sidechain amino acid which lacks the thioether.[10] 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 the fact it is used in the cofactor

S-adenosylmethionine (SAM-e).[11] This situation is not unique and may have occurred with ornithine and arginine.[12]

Encoding

Methionine is one of only two amino acids encoded by a single

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.[13][14]

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

S-Adenosylmethionine is a cofactor derived from methionine.

The methionine-derivative

cobalamin (vitamin B12 in humans). Some enzymes use SAM-e to initiate a radical reaction; these are called radical SAM-e
enzymes. As a result of the transfer of the methyl group, S-adenosylhomocysteine is obtained. In bacteria, this is either regenerated by methylation or is salvaged by removing the adenine and the homocysteine, leaving the compound dihydroxypentandione to spontaneously convert into autoinducer-2, which is excreted as a waste product or quorum signal.

Biosynthesis

Methionine biosynthesis

As an essential amino acid, methionine is not synthesized

α-aminoadipate). The main backbone is derived from aspartic acid, while the sulfur may come from cysteine, methanethiol, or hydrogen sulfide.[9]

  • First, aspartic acid is converted via β-aspartyl semialdehyde into homoserine by two reduction steps of the terminal carboxyl group (homoserine has therefore a γ-hydroxyl, hence the homo- series). The intermediate aspartate semialdehyde is the branching point with the lysine biosynthetic pathway, where it is instead condensed with pyruvate. Homoserine is the branching point with the threonine pathway, where instead it is isomerised after activating the terminal hydroxyl with phosphate (also used for methionine biosynthesis in plants).[9]
  • Homoserine is then activated with a phosphate, succinyl or an acetyl group on the hydroxyl.
    • In plants and possibly in some bacteria,[9] phosphate is used. This step is shared with threonine biosynthesis.[9]
    • In most organisms, an acetyl group is used to activate the homoserine. This can be catalysed in bacteria by an enzyme encoded by metX or metA (not homologues).[9]
    • In enterobacteria and a limited number of other organisms, succinate is used. The enzyme that catalyses the reaction is MetA and the specificity for acetyl-CoA and succinyl-CoA is dictated by a single residue.[9] The physiological basis for the preference of acetyl-CoA or succinyl-CoA is unknown, but such alternative routes are present in some other pathways (e.g. lysine biosynthesis and arginine biosynthesis).
  • The hydroxyl activating group is then replaced with cysteine, methanethiol, or hydrogen sulfide. A replacement reaction is technically a γ-
    Michael addition. All the enzymes involved are homologues and members of the Cys/Met metabolism PLP-dependent enzyme family, which is a subset of the PLP-dependent fold type I clade. They utilise the cofactor PLP (pyridoxal phosphate), which functions by stabilising carbanion intermediates.[9]
  • If homocysteine is produced, the thiol group is methylated, yielding methionine. Two
    cobalamin (vitamin B12) dependent and one is independent.[9]

The pathway using cysteine is called the "transsulfuration pathway", while the pathway using hydrogen sulfide (or methanethiol) is called "direct-sulfurylation pathway".

Cysteine is similarly produced, namely it can be made from an activated serine and either from homocysteine ("reverse transsulfurylation route") or from hydrogen sulfide ("direct sulfurylation route"); the activated serine is generally O-acetylserine (via CysK or CysM in E. coli), but in Aeropyrum pernix and some other archaea O-phosphoserine is used.[15] 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:

  1. Aspartokinase
  2. Aspartate-semialdehyde dehydrogenase
  3. Homoserine dehydrogenase
  4. Homoserine O-transsuccinylase
  5. Cystathionine-γ-synthase
  6. Cystathionine-β-lyase
  7. homocysteine methyltransferase or betaine—homocysteine S-methyltransferase
    .)

Other biochemical pathways

Fates of methionine

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

Catabolism

Methionine is converted to

methionine adenosyltransferase
.

SAM-e serves as a methyl donor in many (2)

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

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.

Ethylene synthesis

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

The Yang cycle

Metabolic diseases

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

Chemical synthesis

The industrial synthesis combines

Racemic methionine can also be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation. Also see Methanol. [17]

Human nutrition

Methionine supplementation benefit those suffering from copper poisoning.[18]

Overconsumption of methionine, the methyl group donor in DNA methylation, is related to cancer growth in a number of studies.[19][20]

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.[21]

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

Dietary sources

Food sources of methionine[citation needed]
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.[22] For that reason, racemic methionine is sometimes added as an ingredient to pet foods.[23]

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.[24] 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.[25]

Methionine is an intermediate in the biosynthesis of cysteine, carnitine, taurine, lecithin, phosphatidylcholine, and other phospholipids. Improper conversion of methionine can lead to atherosclerosis[26] 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.[27]

Methionine is allowed as a supplement to organic poultry feed under the US certified organic program.[28]

Methionine can be used as a nontoxic pesticide option against giant swallowtail caterpillars, which are a serious pest to orange crops.[29]

See also

References

  1. ^ Dawson RM, Elliott DC, Elliott WH, Jones KM (1959). Data for Biochemical Research. Oxford: Clarendon Press.
  2. ..
  3. ^ "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.
  4. ^ "Methionine". Oxford University Press. Archived from the original on January 27, 2018.
  5. ^ Pappenheimer AM (1987). "A Biographical Memoir of John Howard Mueller" (PDF). Washington D.C.: National Academy of Sciences.
  6. ISSN 1881-1272
    .
  7. .
  8. .
  9. ^ .
  10. .
  11. .
  12. .
  13. .
  14. .
  15. .
  16. .
  17. ^ Barger G, Weichselbaum TE (1934). "dl-Methionine". Organic Syntheses. 14: 58; Collected Volumes, vol. 2, p. 384.
  18. ^ "Methionine". WebMD.
  19. PMID 22342103
    .
  20. .
  21. .
  22. .
  23. .
  24. .
  25. .
  26. .
  27. ^ Grimshaw, Jane (July 25, 2011) Methionine for Dogs uses and Side Effects. critters360.com
  28. ^ "Rules and Regulations". Federal Register. 76 (49): 13501–13504. March 14, 2011.
  29. S2CID 45255198
    .

External links