Methylation, biological

Aqueous-Phase Organometallic Catalysis, Second Edition 

Copyright 2004 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim 

During the course of biomethylation the methyl group is most likely transferred as a bridging intermediate rather than a free entity. Such an intermediate is assumed to form during an associative mechanism [4]. The methyl group may be electrophilic (cationic), radical or nucleophilic (anionic), depending on the specific donor moiety. A broad variety of methyl transfer reactions are therefore possible. Besides the two biological donors, methylcobalamin (see below) and S-adenosyl-methonine (1) nonenzymatic transmethylation is also possible in the natural environment, probably also very important for the formation and decomposition of metal methyl compounds [3b], 

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Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

Sulfides and disulfides can be produced by bacterial reactions in the marine environment. 2-Dimeth-ylthiopropionic acid is produced by algae and by the marsh grass Spartina alternifolia, and may then be metabolized in sediment slurries under anoxic conditions to dimethyl sulfide (Kiene and Taylor 1988), and by aerobic bacteria to methyl sulfide (Taylor and Gilchrist 1991). Further details are given in Chapter 11, Part 2. Methyl sulfide can also be produced by biological methylation of sulfide itself (HS ). Carbon radicals are not the initial atmospheric products from organic sulfides and disulfides, and the reactions also provide an example in which the rates of reaction with nitrate... 

Landner L (1971) Biochemical model for biological methylation of mercury suggested from methylation studies in-vivo with Neurospora crassa. Nature 230 452-454. 

Thayer JS (2002) Biological methylation of less-studied elements. Appl Organometal Chem 16 677-691. 

Biological Methylation A Biological Nucleophilic Substitution Reaction... 

It is now well established that organometallic compounds are formed in the environment from mercury, arsenic, selenium, tellurium and tin and hence were also deduced on the basis of analytical evidence for lead, germanium, antimony and thallium. Biological methylation of tin has been demonstrated by the use of experimental organisms. Methylgermanium and methyllead were widely found in the environment but it is debatable whether germanium and lead are directly methylated by biological activity in natural environment. 

Chau and Wong121 observed biological methylation of inorganic lead and of trimethyl-lead acetate in the presence of eleven different sediments as shown in Table 21. The conversion of Me3PbOAc was observed in all experiments but that of lead nitrate was only sporadic. 

Berman, M. and R. Bartha. 1986. Levels of chemical versus biological methylation of mercury in sediments. Bull. Environ. Contam. Toxicol. 36 401-404. 

Rapsomankis et al. [86] have studied the biological methylation of inorganic tin in soils and sediments. 

Chau, Y.K. (1980) Biological methylation of tin compounds in the aquatic environment. 3rd International Conference Organometal Coordinating Chem. Germanium, Tin, Lead, July 1980, University of Dortmund, West Germany. 

Challenger F, Simpson M (1948) Studies on biological methylation. Part 12. A precursor of the dimethyl sulphide evolved by Polysiphonia fastigiata. Dimethyl-2-carboxyethylsulphonium hydroxide and its salts. J Chem Soc 3 1591-1597 Charlson RJ, Lovelock JE, Andreae MO, Warren SG (1987) Oceanic phytoplankton, atmospheric sulphur, cloud albedo and climate. Nature 326 655-661 Coley PD, Aide T (1991) Comparison of herbivory and plant defenses in temperate and tropical broad-leaved forests. In Price P, Lewinsohn T, Fernandes G, Benson W (eds) Plant-animal interactions evolutionary ecology in tropical and temperate regions. Wileys, New York, pp 25 19... 

Selenium has a complex chemistry in the environment because of its multiple oxidation states and variable surface adsorption properties. Qualitatively it is analogous to sulfur occurring in the oxidation states +6 (selenate, Se04 ), +4 (selenite, SeOs "), 0 (elemental selenium) and —2 (Se, selenide) The Se anion closely resembles S (radii 0.20 and 0.185nm, respectively) and is often associated with sulfide minerals. Also, like S, Se is subject to volatilization through biological methylation. 

In biological methylation, the 5-methyl group of the amino acid L-methionine is used to methylate suitable O, N, S, and C nucleophiles. First, methionine is converted into the methylating agent S-adenosylmethionine (SAM). SAM is nucleoside derivative (see Section 14.3). Both the formation of SAM and the subsequent methylation reactions are nice examples of biological Sn2 reactions. 

Now we have seen that the usual reagent for biological methylations is S-adenosylmethionine (SAM) (see Box 6.4). One occasion where SAM is not employed, for fairly obvious reasons, is the regeneration of methionine from homocysteine, after a SAM methylation. For this, A -methyl-FH4 is the methyl donor, with vitamin B12 (see Box 11.4) also playing a role as coenzyme. 

SAM, S-adenosylmethionine, has been encountered as a biological methylating agent, carrying out its function via a simple Sn2 reaction (see Box 6.5). This material is a nucleoside derivative formed by nucleophilic attack of the thiol group of methionine on to ATP (see Box 6.5). It provides in its structure an excellent leaving group, the neutral S-adenosylhomocysteine. 

Mercury dimethyl is a toxic environmental pollutant. It is found in polluted bottom sediments and in the bodies of fishes and birds. In the bodies of fishes and birds it occurs along with monomethyl mercury. The latter, as CH3Hg+ ion, is formed by microorganism-induced biological methylation of elemental mercury or agricultural fungicide mercury compounds that are discharged into the environment. 

Adenosylmethionine (SAM) is a donor of a methyl group in numerous biological methylations. It is first transformed into 5-adenosylhomocysteine (SAH), then into adenosine and homocysteine by SAH hydrolase. 

This type of alkylation also occurs in nature. For example, S-adenosylmethionine (SAM), an important biological methylation reagent, is involved in the biosynthesis of the antibiotic indolmycin and is responsible for the enantioselective C-methylation of an a-oxocarboxylic acid arising from tryptophan3. 

Since S-adenosylmethionine, an important biological methylation agent (see Introduction), has a sugar substituent at the a-position to the sulfur atom, sulfonium salts containing a sugar group have also been used as alkylation agents12. 

Although tetrahydrofolate can carry a methyl group at N-5, the transfer potential of this methyl group is insufficient for most biosynthetic reactions. S -Adenosyl-methionine (adoMet) is the preferred cofactor for biological methyl group transfers. It is synthesized from ATP and methionine by the action of methionine... 

Sulfonium salts are not often employed as reagents for quater-nization. It is therefore interesting to note that the primary biological methylating reagent is the sulfonium salt S-adenosylmethionine (9).30,31... 

Thayer, J. S. Brinkman, F. E. (1982). The biological methylation of metals and metalloids. Advances in Organometallic Chemistry, 20, 313-57. 

S-adenosylmethionine is also a biological methyl group donor. The product of its methyl transferase reactions is S-adenosylhomocysteine. This product is further degraded by S-adenosylhomocysteine hydrolase, an enzyme that contains tightly bound NAD+, to form homocysteine and adenosine. 

Step (v), conversion of [Fe(NO)2(SMe)2] to the product [Fe2(SMe)2(NO)4], occurs spontaneously under the appropriate conditions of solvent polarity/polarizability (23) [cf. Eq. (20) and Schemes 3 and 4], Step(vi) requires the methylation of [Fe2S2(NO)4]2 " while this has been demonstrated for methylation by methyl halides (3, 24, 29), methylation by biological methyl transfer, e.g., from methionine or S-adenosylmethionine, has yet to be investigated. Thus, although neither of the biosynthetic routes suggested in Scheme 5 has yet been fully investigated, several of the steps [(i), (ii), and (vi)], are established, while others [(iv) and (vi)] are already known to occur under nonbiological conditions. 

The term biological methylation originated with Challenger (1-3), although the concept had previously been mentioned by Hofmeister (4). Challenger summarized the concept as follows (3) ... 

For the purposes of this chapter, we shall use the term biological methylation (in recent years this has frequently been contracted to biomethy-lation ) in Challenger s first sense to describe methyl-transfer (transmethylation) reactions involving metals and metalloids in biological systems. We shall not differentiate between endo- and exocellular transmethylation (5, 6), and we shall include some purely chemical studies of model reactions. The relationship of these reactions to the larger area of organometallic chemistry has been reviewed (7, 8). 

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