Methionine was first isolated in 1921 byJohn Howard Mueller.[5] It isencoded by thecodon 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 asMet orM; encoded by the codon AUG) is an α-amino acid that is used in thebiosynthesis ofproteins. It contains acarboxyl group (which is in the deprotonated −COO− form under biologicalpH conditions), anamino group (which is in theprotonated−NH+ 3 form under biological pH conditions) located in α-position with respect to the carboxyl group, and anS-methylthioether side chain, classifying it as anonpolar,aliphatic amino acid.[citation needed]
Cysteine and methionine are the twosulfur-containingproteinogenic amino acids. Excluding the few exceptions where methionine may act as aredox 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 ofS/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 bynorleucine, 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 its role in the cofactorS-adenosylmethionine (rSAM).[11] This situation is not unique and may have occurred withornithine andarginine.[12]
Methionine is one of only two amino acids encoded by a singlecodon (AUG) in the standardgenetic code (tryptophan, encoded by UGG, is the other). In reflection to the evolutionary origin of its codon, the other AUN codons encodeisoleucine, which is also a hydrophobic amino acid. In the mitochondrial genome of several organisms, includingmetazoa andyeast, the codon AUA also encodes for methionine. In the standard genetic code AUA codes for isoleucine and the respective tRNA (ileX inEscherichia coli) uses the unusual baselysidine (bacteria) oragmatidine (archaea) to discriminate against AUG.[13][14]
The methionine-derivativeS-adenosylmethionine (rSAM) is acofactor that serves mainly as amethyl donor. rSAM is composed of an adenosyl molecule (via 5′ carbon) attached to the sulfur of methionine. It is asulfonium cation that releases a methyl radical upon reduction.[15]
As an essential amino acid, methionine is not synthesizedde novo in humans and other animals, which must ingest methionine or methionine-containing proteins. In plants and microorganisms, methionine biosynthesis belongs to theaspartate family, along with threonine andlysine (viadiaminopimelate, but not viaα-aminoadipate). The main backbone is derived fromaspartic acid, while the sulfur may come fromcysteine,methanethiol, orhydrogen sulfide.[9]
First, aspartic acid is converted via β-aspartyl semialdehyde intohomoserine by two reduction steps of the terminal carboxyl group (homoserine has therefore a γ-hydroxyl, hence thehomo- series). The intermediate aspartate semialdehyde is the branching point with the lysine biosynthetic pathway, where it is insteadcondensed 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 bymetX ormetA (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 aMichael addition. All the enzymes involved are homologues and members of theCys/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 producescystathionine, which is cleaved to yieldhomocysteine. The enzymes involved arecystathionine-γ-synthase (encoded bymetB in bacteria) andcystathionine-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 byO-acetylhomoserine aminocarboxypropyltransferase (formerly known asO-acetylhomoserine (thiol)-lyase. It is encoded by eithermetY ormetZ 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. Twomethionine synthases are known; one iscobalamin (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 generallyO-acetylserine (via CysK or CysM inE. coli), but inAeropyrum pernix and some other archaeaO-phosphoserine is used.[16] CysK and CysM are homologues, but belong to the PLP fold type III clade.[citation needed]
Homocysteine can also be remethylated usingglycine betaine (N,N,N-trimethylglycine, TMG) to methionine via the enzymebetaine-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.[citation needed]
Reverse-transulfurylation pathway: conversion to cysteine
The industrial synthesis combinesacrolein,methanethiol, and cyanide, which affords thehydantoin.[17]Racemic methionine can also be synthesized from diethyl sodium phthalimidomalonate by alkylation with chloroethylmethylsulfide (ClCH2CH2SCH3) followed by hydrolysis and decarboxylation. Also see Methanol.[18]
The Food and Nutrition Board of the U.S. Institute of Medicine set Recommended Dietary Allowances (RDAs) foressential 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.[citation needed]
High levels of methionine can be found in eggs, meat, and fish; sesame seeds, Brazil nuts, and some other plant seeds; andcereal grains. Most fruits and vegetables contain very little. Mostlegumes, though protein dense, are low in methionine. Proteins without adequate methionine are not considered to becomplete proteins.[23] For that reason, racemic methionine is sometimes added as an ingredient topet foods.[24]
Loss of methionine has been linked to senile greying of hair. Its lack leads to a buildup ofhydrogen peroxide inhair follicles, a reduction intyrosinase effectiveness, and a gradual loss of hair color.[25] Methionine raises the intracellular concentration ofglutathione, thereby promoting antioxidant-mediated cell defense and redox regulation. It also protects cells againstdopamine 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 againstgiant 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.
^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.
^Holliday GL, Akiva E, Meng EC, Brown SD, Calhoun S, Pieper U, Sali A, Booker SJ, Babbitt PC (2018). "Atlas of the Radical SAM Superfamily: Divergent Evolution of Function Using a "Plug and Play" Domain".Radical SAM Enzymes. Methods in Enzymology. Vol. 606. pp. 1–71.doi:10.1016/bs.mie.2018.06.004.ISBN978-0-12-812794-0.PMC6445391.PMID30097089.
^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.
^Pinnen F, et al. (2009). "Codrugs linkingL-dopa and sulfur-containing antioxidants: new pharmacological tools against Parkinson's disease".Journal of Medicinal Chemistry.52 (2):559–63.doi:10.1021/jm801266x.PMID19093882.
^Refsum H, Ueland PM, Nygård O, Vollset SE (1998). "Homocysteine and cardiovascular disease".Annual Review of Medicine.49 (1):31–62.doi:10.1146/annurev.med.49.1.31.PMID9509248.
