Methyl donor

In cat food, methionine may substitute for choline as methyl donor at a rate of 3.75 parts for 1 part choline by weight when methionine exceeds 0.62%. 

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. 

When acting as a methyl donor, 5-adenosylmethionine forms homocysteine, which may be remethylated by methyltetrahydrofolate catalyzed by methionine synthase, a vitamin Bj2-dependent enzyme (Figure 45-14). The reduction of methylene-tetrahydrofolate to methyltetrahydrofolate is irreversible, and since the major source of tetrahydrofolate for tissues is methyl-tetrahydrofolate, the role of methionine synthase is vital and provides a link between the functions of folate and vitamin B,2. Impairment of methionine synthase in Bj2 deficiency results in the accumulation of methyl-tetrahydrofolate—the folate trap. There is therefore functional deficiency of folate secondary to the deficiency of vitamin B,2. 

Methylation— A few xenobiotics are subject to methylation by methyltransferases, employing 5-adeno-sylmethionine (Figure 30-17) as the methyl donor. 

Despite our earlier failure in formate feeding experiments, [3- C]serine, [1,2- CJglycine, and [Me- C]methionine were found to enrich C-13 in neosaxitoxin effectively (7). The best incorporation was observed with methionine, indicating it is the direct precursor via S-adenosylmethionine. Glycine C-2 and serine C-3 must have been incorporated through tetrahydrofolate system as methyl donors in methionine biosynthesis. 

The possibility that synthesis of the HGA in tobacco membranes might be limited by the lack of methyl donor was ruled out since the addition of exogenous S-adenosylmethionine, a methyl donor known to function in the methylesterification of pectin (41,70), did not... 

Under aerobic conditions, S -adenosyhnethionine is the methyl donor for methylation of meth-anethiol and methaneselenol (Drotar et al. 1987), and probably for the bacterial methylation of halogenated phenols and thiophenols (Neilson et al. 1988). It is also the probable methyl donor for fungal methylation of the oxyanions of As and Sb (Bentley and Chasteen 2002). 

DMSP (21) is produced by many marine micro- and macroalgae and is especially prominent in dinoflagellates and haptophytes. The nontoxic DMSP (21) fulfills multiple cellular functions including cryoprotection, the involvement as osmolyte in osmoregulation and as a methyl donor in transmethylation reactions [18]. 

In 1995, Horie et al. described a polymorphic tandem repeat found in the 5 -un-translated region of the thymidylate synthase gene [70]. Thymidylate synthase (TS TYMS) catalyzes the intracellular transfer of a methyl group to deoxyuridine-5-monophosphate (dUMP) to form deoxythymidine-5-monophosphate (dTMP), which is anabolized in cells to the triphosphate (dTTP). This pathway is the only de- novo source of thymidine, an essential precursor for DNA synthesis and repair. The methyl donor for this reaction is the folate cofactor 5,10-methylenetetrahydro-folate (CH2-THF) (Figure 24.4). 

The transsulfuration pathway (Fig. 40-4) entails the transfer of the sulfur atom of methionine to serine to yield cysteine. The first step is activation of methionine, which reacts with ATP to form S-adenosylmethionine (Fig. 40-4 reaction 1). This compound is a key methyl donor and plays a prominent role in the synthesis of several... 

About half of the homocysteine so generated is remethylated to methionine, with either betaine or 5-methyltetra-hydrofolic acid (methyl-FH4) serving as methyl donor. 

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the NAD(P)H-dependent reduction of 5,10-methylenetetrahydrofolate (CH2-THF) to 5-methyltetrahydrofolate (CH3-THF). CH3-THF then serves as a methyl donor for the synthesis of methionine. The MTHFR proteins and genes from mammalian liver and E. coli have been characterized,12"15 and MTHFR genes have been identified in S. cerevisiae16 and other organisms. The MTHFR of E. coli (MetF) is a homotetramer of 33-kDa subunits that prefers NADH as reductant,12 whereas mammalian MTHFRs are homodimers of 77-kDa subunits that prefer NADPH and are allosterically inhibited by AdoMet.13,14 Mammalian MTHFRs have a two-domain structure the amino-terminal domain shows 30% sequence identity to E. coli MetF, and is catalytic the carboxyterminal domain has been implicated in AdoMet-mediated inhibition of enzyme activity.13,14... 

The best characterized B 12-dependent methyltransferases is methionine synthase (Figure 15.11) from E. coli, which catalyses the transfer of a methyl group from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate. During the catalytic cycle, B12 cycles between CH3-Co(in) and Co(I). However, from time to time, Co(I) undergoes oxidative inactivation to Co(II), which requires reductive activation. During this process, the methyl donor is S-adenosylmethionine (AdoMet) and the electron donor is flavodoxin (Fid) in E. coli, or methionine synthase reductase (MSR) in humans. Methionine synthase... 

Several papers have commented that DMSP may function as a methyl donor (Challenger and Simpson 1948 Dubnoff and Borsook 1948 Visscher et al. 1994 Marc et al. 1995 Kirst 1996), but the importance of this process in marine macroalgae is not known. Marine bacteria can demethylate DMSP to methanethiol via 3-methiolpropionate or following the cleavage of DMSP into DMS and acrylate (Kiene and Taylor 1988 Taylor and Gilchrist 1991 Gonzalez et al. 1999) however, the fate of the methyl groups was not determined in these studies. 

The mechanism of transmethylation was then examined. A series of deuterium-labeled methylated compounds were synthesized by du Vigneaud s group, including arsenocholine, trimethylamine, dimethyl-glycine, and dimethylthetin. Of these only betaine and dimethylthetin served as methyl donors. In 1949 Dubnoff found that choline could only act as a donor under aerobic conditions, when it was oxidized to betaine. 

The final step in our understanding of transmethylation followed from the observation by Cantoni (1951) that betaine and dimethylthetin only acted as methyl donors in the presence of homocysteine, i.e. after the methyl group had been transferred to give methionine. Methionine would only transmethylate if ATP was available. S-adenosyl methionine was therefore proposed as the primary methyl donor, a suggestion confirmed after the compound had been synthesized by Baddiley and Jamieson in 1954. 

Some of the catecholamine will enter the target cell rather than be recaptured by the neurone. Inactivation is brought about by the second enzyme, COMT which uses S-adenosyl methionine as a methyl donor as does PNMT (involved with catecholamine... 

Histone methylation is another posttranslational modification which involves a transfer of a methyl group from the methyl donor S-adenosyl methionine (SAM) to lysine or arginine residues (Fig. 1). In sharp contrast with histone acetylation, this modification occurs particularly in histones H3 and H4 with a remarkable specificity (Kouzarides, 2002 Shilatifard, 2006) (Fig. 1, Table 2). Another feature of histone methylation is that a large fraction of histones in mature chromatin is... 

Methionine (Met or M) ((5)-2-amino-4-(methylsulfanyl)-butanoic acid) is a nonpolar, neutral, amino acid with the formula HOOCCH(NH2)CH2CH2SCH3. Together with Cys, Met is one of the two sulfur-containing proteinogenic amino acids and a great antioxidant. Its derivative 5-adenosyl methionine (SAM) serves as a methyl donor. ... 

Methionine, another sulfur-containing amino acid, is part of S-adenosylmethionine (SAM), a methyl donor in biochemical pathways. 

One-carbon units in different oxidation states are required in the pathways producing purines, thymidine, and many other compounds. When a biochemical reaction requires a methyl group (methylation), S-adenos dmethionme (SAM) is generally the methyl donor. If a one-carbon unit in another oxidation state is required (methylene, methenyl, formyl), tetrahydrofolate (THF) typically serves as its donor. 

Additional folate may be stored as the highly reduced JV -methyl-THF. This form is referred to as the storage pool as there is only one known enzyme that uses it, and in turn moves it back into the active pool. This enzyme is N-methyl THF-homocysteine methyltransferase, discussed above, which also requires vitamin and is involved in regenerating SAM as a methyl donor for reactions. 

Figure 15.5 Four reactions involved in methylatlon. The reactions are (1) formation of S-adenosylmethlonIne (SAM) (11) transfer of methyl group to an acceptor (111) conversion of S-adenosylmethlonIne to homocysteine (Iv) conversion of homocysteine to methionine using methyl tetrahydrofolate as the methyl donor with the formation of FH4.

Histone-lysine methyltransferases are chromatin-bound enzymes that catalyses the addition of methyl groups onto lysine or arginine residues of chromatin-bound H3 and H4 [151]. The methyl group is transferred enzymatically to the histone with S-adenosyl methionine as the methyl donor. Histone methylases have been isolated from HeLa S-3 cells [182], chick embryo nuclei [183], and rat brain chromatin [184]. The histone methyltransferases methylated H3 and H4 in nucleosomes [184]. Histone-lysine methyltransferase is a chromatin-bound enzyme [129,151]. Initial characterization of the Tetrahymena macronuclear H3 methyltransferase suggests that the enzyme has a molecular mass of 400 kDa. The enzyme preferred free histones rather than nucleosomes as substrate [138]. More recent studies have now... 

Plant sterols such as stigmasterol typically contain an extra ethyl group when compared with cholesterol. Now this is not introduced by an electrophilic ethylation process instead, two successive electrophilic methylation processes occur, both involving SAM as methyl donor. Indeed, it is a methylene derivative like that just seen in ergosterol formation that can act as the alkene for further electrophilic alkylation. After proton loss, the product has a side-chain with an ethylidene substituent the side-chains of the common plant sterols stigmasterol and sitosterol are then related by repeats of the reduction and dehydrogenation processes already seen in ergosterol formation. 

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