As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds 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 John Howard Mueller.[5] 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.[6]
Methionine (abbreviated as MetorM; encoded by the codon AUG) is an α-amino acid that is used in the biosynthesisofproteins. It contains a carboxyl group (which is in the deprotonated −COO− form under biological pH conditions), an amino group (which is in the protonated−NH+ 3 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.
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]
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 (ileXinEscherichia coli) uses the unusual base lysidine (bacteria) or agmatidine (archaea) to discriminate against AUG.[13][14]
The methionine-derivative S-adenosylmethionine (SAM-e) is a cofactor that serves mainly as a methyl donor. SAM-e is composed of an adenosyl molecule (via 5′ carbon) attached to the sulfur of methionine, therefore making it a sulfonium cation (i.e., three substituents and positive charge). The sulfur acts as a soft Lewis acid (i.e., donor/electrophile) which allows the S-methyl group to be transferred to an oxygen, nitrogen, or aromatic system, often with the aid of other cofactors such as 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.
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.[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 metXormetA (not homologues).[9]
Inenterobacteria 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-elimination followed by a variant of a 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 it reacts with cysteine, it produces cystathionine, which is cleaved to yield homocysteine. The enzymes involved are cystathionine-γ-synthase (encoded by metB in bacteria) and cystathionine-β-lyase (metC). Cystathionine is bound differently in the two enzymes allowing β or γ reactions to occur.[9]
If it reacts with free hydrogen sulfide, it produces homocysteine. This is catalysed by O-acetylhomoserine aminocarboxypropyltransferase (formerly known as O-acetylhomoserine (thiol)-lyase. It is encoded by either metYormetZ in bacteria.[9]
If it reacts with methanethiol, it produces methionine directly. Methanethiol is a byproduct of catabolic pathway of certain compounds, therefore this route is more uncommon.[9]
If homocysteine is produced, the thiol group is methylated, yielding methionine. Two methionine synthases are known; one is 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.
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[edit]
The industrial synthesis combines acrolein, methanethiol, and cyanide, which affords the hydantoin.[16]Racemic methionine can also be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation. Also see Methanol. [17]
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.[22]
This translates to about 1.33 grams per day for a 70 kilogram individual.
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.[23] For that reason, racemic methionine is sometimes added as an ingredient to pet foods.[24]
Loss of methionine has been linked to senile greying of hair. Its lack leads to a buildup of hydrogen peroxideinhair follicles, a reduction in tyrosinase effectiveness, and a gradual loss of hair color.[25] 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.[26]
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.[28]
Methionine is allowed as a supplement to organic poultry feed under the US certified organic program.[29]
Methionine can be used as a nontoxic pesticide option against giant swallowtail caterpillars, which are a serious pest to orange crops.[30]
^Cirino PC, Tang Y, Takahashi K, Tirrell DA, Arnold FH (September 2003). "Global incorporation of norleucine in place of methionine in cytochrome P450 BM-3 heme domain increases peroxygenase activity". Biotechnology and Bioengineering. 83 (6): 729–734. doi:10.1002/bit.10718. PMID12889037. S2CID11380413.
^Alvarez-Carreño C, Becerra A, Lazcano A (October 2013). "Norvaline and norleucine may have been more abundant protein components during early stages of cell evolution". Origins of Life and Evolution of the Biosphere. 43 (4–5): 363–375. Bibcode:2013OLEB...43..363A. doi:10.1007/s11084-013-9344-3. PMID24013929. S2CID17224537.
^Jukes TH (August 1973). "Arginine as an evolutionary intruder into protein synthesis". Biochemical and Biophysical Research Communications. 53 (3): 709–714. doi:10.1016/0006-291x(73)90151-4. PMID4731949.
^Ikeuchi Y, Kimura S, Numata T, Nakamura D, Yokogawa T, Ogata T, Wada T, Suzuki T, Suzuki T (April 2010). "Agmatine-conjugated cytidine in a tRNA anticodon is essential for AUA decoding in archaea". Nature Chemical Biology. 6 (4): 277–282. doi:10.1038/nchembio.323. PMID20139989.
^Muramatsu T, Nishikawa K, Nemoto F, Kuchino Y, Nishimura S, Miyazawa T, Yokoyama S (November 1988). "Codon and amino-acid specificities of a transfer RNA are both converted by a single post-transcriptional modification". Nature. 336 (6195): 179–181. Bibcode:1988Natur.336..179M. doi:10.1038/336179a0. PMID3054566. S2CID4371485.
^ abNavik U, Sheth VG, Khurana A, Jawalekar SS, Allawadhi P, Gaddam RR, Bhatti JS, Tikoo K. (2021). "Methionine as a double-edged sword in health and disease: Current perspective and future challenges". Ageing Res Rev. 72: 101500. doi:10.1016/j.arr.2021.101500. PMID34700006.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Cavuoto P, Fenech MF (2012). "A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension". Cancer Treatment Reviews. 38 (6): 726–736. doi:10.1016/j.ctrv.2012.01.004. PMID22342103.
^Cellarier E, Durando X, Vasson MP, Farges MC, Demiden A, Maurizis JC, Madelmont JC, Chollet P (2003). "Methionine dependency and cancer treatment". Cancer Treatment Reviews. 29 (6): 489–499. doi:10.1016/S0305-7372(03)00118-X. PMID14585259.
^Palika L (1996). The Consumer's Guide to Dog Food: What's in Dog Food, Why It's There and How to Choose the Best Food for Your Dog. New York: Howell Book House. ISBN978-0-87605-467-3.
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