HOME

TheInfoList



OR:

In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of
alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
, with a methyl group replacing a
hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-to ...
atom. These terms are commonly used in
chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, structure, proper ...
,
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
,
soil science Soil science is the study of soil as a natural resource on the surface of the Earth including soil formation, classification and mapping; physical, chemical, biological, and fertility properties of soils; and these properties in relation to ...
, and the biological sciences. In
biological systems A biological system is a complex network which connects several biologically relevant entities. Biological organization spans several scales and are determined based different structures depending on what the system is. Examples of biological syst ...
, methylation is catalyzed by
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s; such methylation can be involved in modification of
heavy metals upright=1.2, Crystals of osmium, a heavy metal nearly twice as dense as lead">lead.html" ;"title="osmium, a heavy metal nearly twice as dense as lead">osmium, a heavy metal nearly twice as dense as lead Heavy metals are generally defined as ...
, regulation of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. T ...
, regulation of
protein function Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respond ...
, and RNA processing. In vitro methylation of tissue samples is also one method for reducing certain histological staining artifacts. The reverse of methylation is demethylation.


In biology

In biological systems, methylation is accomplished by enzymes. Methylation can modify heavy metals, regulate gene expression, RNA processing and protein function. It has been recognized as a key process underlying
epigenetics In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...
.


Methanogenesis

Methanogenesis, the process that generates methane from CO2, involves a series of methylation reactions. These reactions are effected by a set of enzymes harbored by a family of anaerobic microbes. In reverse methanogenesis, methane serves as the methylating agent.


O-methyltransferases

A wide variety of phenols undergo O-methylation to give
anisole Anisole, or methoxybenzene, is an organic compound with the formula CH3OC6H5. It is a colorless liquid with a smell reminiscent of anise seed, and in fact many of its derivatives are found in natural and artificial fragrances. The compound i ...
derivatives. This process, catalyzed by enzymes such as
caffeoyl-CoA O-methyltransferase In enzymology, a caffeoyl-CoA O-methyltransferase () is an enzyme that catalyzes the chemical reaction :S-adenosyl-L-methionine + caffeoyl-CoA \rightleftharpoons S-adenosyl-L-homocysteine + feruloyl-CoA Thus, the two substrates of this enzyme ...
, is a key reaction in the biosynthesis of lignols, percursors to
lignin Lignin is a class of complex organic polymers that form key structural materials in the support tissues of most plants. Lignins are particularly important in the formation of cell walls, especially in wood and bark, because they lend rigidity a ...
, a major structural component of plants. Plants produce flavonoids and isoflavones with methylations on hydroxyl groups, i.e. methoxy bonds. This 5-O-methylation affects the flavonoid´s water solubility. Examples are
5-O-methylgenistein 5-''O''-Methylgenistein is an O-methylated isoflavone. It can be found in ''Ormosia excelsa ''Ormosia excelsa'' is a plant species in the genus ''Ormosia'', a tropical legume. ''Ormosia excelsa'' produces the O-methylated isoflavone 5-O-meth ...
,
5-O-methylmyricetin 5-''O''-Methylmyricetin is an ''O''-methylated flavonol, a type of flavonoid. It is the 5-''O''-methyl derivative of myricetin Myricetin is a member of the flavonoid class of polyphenolic compounds, with antioxidant properties. Common dietar ...
or
5-O-methylquercetin Azaleatin is a chemical compound. It is an O-methylated flavonol, a type of flavonoid. It was first isolated from the flowers of ''Rhododendron mucronatum'' in 1956 and has since been recorded in forty-four other Rhododendron species, in ''Plumbag ...
, also known as azaleatin.


Proteins

Together with ubiquitin and phosphorylation, methylation is a major biochemical process for modifying protein function. The most prevalent protein methylations affect arginine and lysine residue of specific histones. Otherwise histidine, glutamate, asparagine, cysteine are susceptible to methylation. Some of these products include ''S''-methylcysteine, two isomers of ''N''-methylhistidine, and two isomers of ''N''-methylarginine.


Methionine synthase

Methionine synthase regenerates methionine (Met) from homocysteine (Hcy). The overall reaction transforms 5-methyltetrahydrofolate (N5-MeTHF) into tetrahydrofolate (THF) while transferring a methyl group to Hcy to form Met. Methionine Synthases can be cobalamin-dependent and cobalamin-independent: Plants have both, animals depend on the methylcobalamin-dependent form. In methylcobalamin-dependent forms of the enzyme, the reaction proceeds by two steps in a ping-pong reaction. The enzyme is initially primed into a reactive state by the transfer of a methyl group from N5-MeTHF to Co(I) in enzyme-bound cobalamin (Cob), forming methyl-cobalamin(Me-Cob) that now contains Me-Co(III) and activating the enzyme. Then, a Hcy that has coordinated to an enzyme-bound
zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
to form a reactive thiolate reacts with the Me-Cob. The activated methyl group is transferred from Me-Cob to the Hcy thiolate, which regenerates Co(I) in Cob, and Met is released from the enzyme.


Heavy metals: arsenic, mercury, cadmium

Biomethylation is the pathway for converting some heavy elements into more mobile or more lethal derivatives that can enter the food chain. The biomethylation of
arsenic Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, b ...
compounds starts with the formation of methanearsonates. Thus, trivalent inorganic arsenic compounds are methylated to give methanearsonate.
S-adenosylmethionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
is the methyl donor. The methanearsonates are the precursors to dimethylarsonates, again by the cycle of reduction (to methylarsonous acid) followed by a second methylation. Related pathways apply to the
biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...
of methylmercury.


Epigenetic methylation


DNA/RNA methylation

DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sitesthat is, where a
cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached ( ...
is directly followed by a
guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is ...
in the DNA sequence). This methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. In mammals, DNA methylation is common in body cells, and methylation of CpG sites seems to be the default. Human DNA has about 80–90% of CpG sites methylated, but there are certain areas, known as
CpG islands The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG i ...
, that are CG-rich (high cytosine and guanine content, made up of about 65% CG residues), wherein none is methylated. These are associated with the promoters of 56% of mammalian genes, including all ubiquitously expressed genes. One to two percent of the human genome are CpG clusters, and there is an inverse relationship between CpG methylation and transcriptional activity. Methylation contributing to epigenetic inheritance can occur through either DNA methylation or protein methylation. Improper methylations of human genes can lead to disease development, including cancer. Similarly, RNA methylation occurs in different RNA species viz.
tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ...
,
rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribos ...
,
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
,
tmRNA Transfer-messenger RNA (abbreviated tmRNA, also known as 10Sa RNA and by its genetic name SsrA) is a bacterial RNA molecule with dual tRNA-like and messenger RNA-like properties. The tmRNA forms a ribonucleoprotein complex (tmRNP) together with Sm ...
, snRNA,
snoRNA In molecular biology, Small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRN ...
, miRNA, and viral RNA. Different catalytic strategies are employed for RNA methylation by a variety of RNA-methyltransferases. RNA methylation is thought to have existed before DNA methylation in the early forms of life evolving on earth. N6-methyladenosine (m6A) is the most common and abundant methylation modification in RNA molecules (mRNA) present in eukaryotes. 5-methylcytosine (5-mC) also commonly occurs in various RNA molecules. Recent data strongly suggest that m6A and 5-mC RNA methylation affects the regulation of various biological processes such as RNA stability and mRNA translation, and that abnormal RNA methylation contributes to etiology of human diseases.


Protein methylation

Protein methylation Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number ...
typically takes place on
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
or lysine
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
residues in the protein sequence. Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (
asymmetric dimethylarginine Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a condit ...
) or one on both nitrogens (symmetric dimethylarginine), by protein arginine methyltransferases (PRMTs). Lysine can be methylated once, twice, or three times by lysine methyltransferases. Protein methylation has been most studied in the
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
s. The transfer of
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
groups from
S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
to histones is catalyzed by enzymes known as
histone methyltransferase Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues ...
s. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression. Protein methylation is one type of
post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribo ...
.


Evolution

Methyl metabolism is very ancient and can be found in all organisms on earth, from bacteria to humans, indicating the importance of methyl metabolism for physiology. Indeed, pharmacological inhibition of global methylation in species ranging from human, mouse, fish, fly, round worm, plant, algae and cyanobacteria causes the same effects on their biological rhythms, demonstrating conserved physiological roles of methylation during evolution.


In chemistry

The term methylation in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J ...
refers to the
alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
process used to describe the delivery of a group.


Electrophilic methylation

Methylations are commonly performed using ''electrophilic'' methyl sources such as iodomethane, dimethyl sulfate, dimethyl carbonate, or
tetramethylammonium chloride Tetramethylammonium chloride is one of the simplest quaternary ammonium salts, with four methyl groups tetrahedrally attached to the central N. The chemical formula (CH3)4N+Cl− is often abbreviated further as Me4N+Cl−. It is a hygroscopic colo ...
. Less common but more powerful (and more dangerous) methylating reagents include methyl triflate, diazomethane, and methyl fluorosulfonate ( magic methyl). These reagents all react via SN2 nucleophilic substitutions. For example, a carboxylate may be methylated on oxygen to give a methyl
ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
; an alkoxide salt may be likewise methylated to give an
ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again ...
, ; or a ketone enolate may be methylated on carbon to produce a new
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double b ...
. : The Purdie methylation is a specific for the methylation at oxygen of
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...
s using iodomethane and silver oxide. :


Eschweiler–Clarke methylation

The Eschweiler–Clarke reaction is a method for methylation of
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
s. This method avoids the risk of quaternization, which occurs when amines are methylated with methyl halides.


Diazomethane and trimethylsilyldiazomethane

Diazomethane and the safer analogue trimethylsilyldiazomethane methylate carboxylic acids, phenols, and even alcohols: :RCO2H + tmsCHN2 + CH3OH -> RCO2CH3 + CH3Otms + N2 The method offers the advantage that the side products are easily removed from the product mixture.


Nucleophilic methylation

Methylation sometimes involve use of ''nucleophilic'' methyl reagents. Strongly nucleophilic methylating agents include methyllithium () or
Grignard reagent A Grignard reagent or Grignard compound is a chemical compound with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromide . ...
s such as methylmagnesium bromide (). For example, will add methyl groups to the carbonyl (C=O) of ketones and aldehyde.: : Milder methylating agents include tetramethyltin,
dimethylzinc Dimethylzinc, also known as Zinc methyl, DMZ, or DMZn is a colorless volatile liquid Zn(CH3)2, formed by the action of methyl iodide on zinc at elevated temperature or on zinc sodium alloy. :2Zn + 2CH3I → Zn(CH3)2 + ZnI2 The sodium assists the ...
, and trimethylaluminium.


See also


Biology topics

*
Bisulfite sequencing Bisulfite sequencing (also known as bisulphite sequencing) is the use of bisulfite treatment of DNA before routine sequencing to determine the pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the mo ...
– the biochemical method used to determine the presence or absence of methyl groups on a DNA sequence *
MethDB MethDB is a database for DNA methylation data. See also * DNA methylation DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the s ...
DNA Methylation Database * Microscale thermophoresis – a biophysical method to determine the methylisation state of DNA


Organic chemistry topics

*
Alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
* Methoxy * Titanium–zinc methylenation * Petasis reagent *
Nysted reagent The Nysted reagent is a reagent used in organic synthesis for the methylenation of a carbonyl group. It was discovered in 1975 by Leonard N. Nysted in Chicago, Illinois. It was originally prepared by reacting dibromomethane and activated zinc in ...
* Wittig reaction * Tebbe's reagent


References


External links


deltaMasses
Detection of Methylations after Mass Spectrometry {{Authority control Epigenetics Organic reactions Post-translational modification