Methylation

In the chemical sciences, methylation denotes the installation of a methyl group on a substrate. Usually methylations entail the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with a methyl group, rather than a larger carbon chain, replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and the biological sciences.

In biological systems, methylation is catalyzed by enzymes; such methylation can be involved in modification of heavy metals, regulation of gene expression, regulation of protein function, and RNA processing. Methylation of heavy metals can also occur outside biological systems. Chemical methylation of tissue samples is also one method for reducing certain histological staining artifacts. The counterpart of methylation is demethylation.

In biology

O-Methyltransferases

A wide variety of phenols undergo O-methylation to give anisole derivatives. This process, catalyzed by enzymes such as caffeoyl-CoA O-methyltransferase, is a key reaction in the biosynthesis of lignols, precursors to lignin, a major structural component of plants.

One step in the biosynthesisof the lignol sinapyl alcohol is methylation.

Methylcobalamin

Methylcobalamin is an important methylating agent in nature.
The methylation reaction catalyzed by methionine synthase.

Methionine synthase catalyzes the final step in the regeneration of 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. 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 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.[1]

DNA methylation

DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites, that is, where a cytosine is directly followed by a guanine 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. Human DNA has about 80–90% of CpG sites methylated, but there are certain areas, known as CpG islands, that are GC-rich (high guanine and cytosine content, made up of about 65% CG residues), wherein none are 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.

Protein methylation

Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence.[2] Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylarginine) or one on both nitrogens (symmetric dimethylarginine) by peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by lysine methyltransferases. Protein methylation has been most studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.[3][4] Protein methylation is one type of post-translational modification.

In chemistry

The term methylation in organic chemistry refers to the alkylation process used to describe the delivery of a CH3 group.[5]

Electrophilic methylation

Methylations are commonly performed using electrophilic methyl sources such as iodomethane,[6] dimethyl sulfate,[7][8] dimethyl carbonate,[9] or tetramethylammonium chloride.[10] Less common but with the more powerful (and more dangerous) methylating reagents include methyl triflate,[11] diazomethane,[12] 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, an alkoxide salt RO− may be likewise methylated to give an ether, ROCH3, or a ketone enolate may be methylated on carbon to produce a new ketone.

Specialized methylation protocols

The Eschweiler-Clarke reaction is a method for methylation of amines.[13] This method avoids the risk of quaternization, which occurs when amines are methylated with methyl halides.

The Purdie methylation is a specific for the methylation at oxygen of carbohydrates using iodomethane and silver oxide.[14]

Nucleophilic methylation

Methylation sometimes involve use of nucleophilic methyl reagents. Strongly nucleophilic methylating agents include methyllithium (CH3Li)[15] or Grignard reagents such as methylmagnesium bromide (CH3MgX).[16] For example, CH3Li will add methyl groups to the carbonyl (C=O) of ketones and aldehyde.:

Milder methylating agents include tetramethyltin, dimethylzinc, and trimethylaluminium.[17]

5-O-methylations

See also

Biology topics

Organic chemistry topics

References

  1. ↑ Matthews, R. G.; Smith, A. E.; Zhou, Z. S.; Taurog, R. E.; Bandarian, V.; Evans, J. C.; Ludwig, M. (2003). "Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases: Are There Two Solutions to the Same Chemical Problem?". Helvetica Chimica Acta 86 (12): 3939–3954. doi:10.1002/hlca.200390329.
  2. ↑ Walsh, Christopher (2006). "Chapter 5 – Protein Methylation" (PDF). Posttranslational modification of proteins: expanding nature's inventory. Roberts and Co. Publishers. ISBN 0-9747077-3-2.
  3. ↑ Grewal, S. I.; Rice, J. C. (2004). "Regulation of heterochromatin by histone methylation and small RNAs". Current Opinion in Cell Biology 16 (3): 230–238. doi:10.1016/j.ceb.2004.04.002. PMID 15145346.
  4. ↑ Nakayama, J. -I.; Rice, J. C.; Strahl, B. D.; Allis, C. D.; Grewal, S. I. (2001). "Role of Histone H3 Lysine 9 Methylation in Epigenetic Control of Heterochromatin Assembly". Science 292 (5514): 110–113. doi:10.1126/science.1060118. PMID 11283354.
  5. ↑ March, Jerry; Smith, Michael W (2001). March's advanced organic chemistry: reactions, mechanisms, and structure. New York: Wiley. ISBN 0-471-58589-0.
  6. ↑ Vyas, G. N.; Shah, N. M. (1951). "Quninacetophenone monomethyl ether". Organic Syntheses 31: 90. doi:10.15227/orgsyn.031.0090.
  7. ↑ Hiers, G. S. (1929). "Anisole". Organic Syntheses 9: 12. doi:10.15227/orgsyn.009.0012.
  8. ↑ Icke, Roland N.; Redemann, Ernst; Wisegarver, Burnett B.; Alles, Gordon A. (1949). "m-Methoxybenzaldehyde". Organic Syntheses 29: 63. doi:10.15227/orgsyn.029.0063.
  9. ↑ Tundo, Pietro; Selva, Maurizio; Bomben, Andrea (1999). "Mono-C-methylathion of arylacetonitriles and methyl arylacetates by dimethyl carbonate: a general method for the synthesis of pure 2-arylpropionic acids. 2-Phenylpropionic acid". Organic Syntheses 76: 169. doi:10.15227/orgsyn.076.0169.
  10. ↑ Nenad, Maraš; Polanc, Slovenko; Kočevar, Marijan (2008). "Microwave-assisted methylation of phenols with tetramethylammonium chloride in the presence of K2CO3 or Cs2CO3". Tetrahedron 64 (51): 11618–11624. doi:10.1016/j.tet.2008.10.024.
  11. ↑ Poon, Kevin W. C.; Albiniak, Philip A.; Dudley, Gregory B. (2007). "Protection of alcohols using 2-benzyloxy-1-methylpyridinium trifluoromethanesulfanonate: Methyl (R)-(-)-3-benzyloxy-2-methyl propanoate". Organic Syntheses 84: 295. doi:10.15227/orgsyn.084.0295.
  12. ↑ Neeman, M.; Johnson, William S. (1961). "Cholestanyl methyl ether". Organic Syntheses 41: 9. doi:10.15227/orgsyn.041.0009.
  13. ↑ Icke, Roland N.; Wisegarver, Burnett B.; Alles, Gordon A. (1945). "β-Phenylethyldimethylamine". Organic Syntheses 25: 89. doi:10.15227/orgsyn.025.0089.
  14. ↑ Purdie, T.; Irvine, J. C. (1903). "C.?The alkylation of sugars". Journal of the Chemical Society, Transactions 83: 1021. doi:10.1039/CT9038301021.
  15. ↑ Lipsky, Sharon D.; Hall, Stan S. (1976). "Aromatic Hydrocarbons from aromatic ketones and aldehydes: 1,1-Diphenylethane". Organic Syntheses 55: 7. doi:10.15227/orgsyn.055.0007.
  16. ↑ Grummitt, Oliver; Becker, Ernest I. (1950). "trans-1-Phenyl-1,3-butadiene". Organic Syntheses 30: 75. doi:10.15227/orgsyn.030.0075.
  17. ↑ Negishi, Ei-ichi; Matsushita, Hajime (1984). ""Palladium-Catalyzed Synthesis of 1,4-Dienes by Allylation of Alkenyalane: α-Farnesene". Organic Syntheses 62: 31. doi:10.15227/orgsyn.062.0031.
  18. ↑ Wienken CJ, Baaske P, Duhr S, Braun D (2011). "Thermophoretic melting curves quantify the conformation and stability of RNA and DNA". Nucleic Acids Research 39 (8): e52–e52. doi:10.1093/nar/gkr035. PMC 3082908. PMID 21297115.

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