Transmethylation carbon methylation

Although the list of transmethylation reactions in which S-adenosylmethionine can function as the methyl donor could now undoubtedly be greatly expanded, the more recently added reactions, with the exception of the carbon methylations discussed below (Section II,C,6), appear from the chemical point of view to be further examples of types of reactions which were already known. Therefore, no complete compilation will be attempted. From the physiological standpoint, on the other hand, some of the reactions recently studied may be of great interest. For example, systems have now been reported for the enzymic methylation of RNA (Srinavasan and Borek, 1964 Rodeh et al, 1967), DNA (Oda and Marmur, 1966 Kalousek and Morris, 1969), pectin (Kauss and Hassid, 1967), and protein (Comb et al, 1966 Paik and Kim, 1968 Liss et al, 1969). The specific modifications of the properties of these biopolymers consequent to methylation may, of course, be important in... 

Biological C-alkylation reactions have attracted considerable experimental attention in recent years. As a result of some early studies, in which it was shown that only two of the three hydrogens attached to the methyl carbon are transferred during certain carbon methylations, it appeared that perhaps new chemical or biochemical principles might be involved. Further investigation has shown however, that carbon methylations may rather comfortably be accommodated within the existing theoretical understanding of transmethylation reactions. For these reasons, it may be worthwhile to discuss this area in some detail. 

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

In addition, GSH dysregulation might play a role in the framework of the Single-Carbon Hypothesis of schizophrenia originally proposed by Smythies et al. (Smythies et al., 1997). In the transmethylation pathway, methionine is converted to homocysteine providing methyl groups to DNA, lipids and proteins. 

Methylation derivatization also has been successfully used for the transmethylation of esters and carbonates. For an ester, the reaction can take place by the following mechanism ... 

Miscellaneous Synthetic compounds - Procarbazine, (N-isopropyl-Of-(2 methylhydrazino)-g -toluamide hydrochloride), one of several derivatives of methylhydrazine which have antineoplastic activity against transplanted tumors, has proven clinically useful in the management of Hodgkin s disease. A second derivative, N-allophanoyl-a-(2 methylhydrazine)- -toluam-ide, appeared to have activity comparable to that of procarbazine in a preliminary clinical trial. 47 The mechanism by which procarbazine and related compounds produce cytotoxicity is not established. Procarbazine produced a short-lived inhibition of synthesis of DNA, RNA and protein when studied in a mouse lymphoma 48 the methyl group enters the 1-carbon pool and participates in transmethylation reactions. 49 Pertinence of these observations, as well as those previously described of molecular autoxidation to the drug s antitumor effects, awaits demonstration. 

Thus the addict is excreting morphine more rapidly in the urine and is converting morphine more rapidly to carbon dioxide than does a normal subject. About 1/17 of the injected morphine is accounted for in the expired air of the addict in 24 hr. and only 1 /30 in the expired air of the normal subject. There has been a 50% increase in the ability of the addict to convert the methyl group of morphine to carbon dioxide as compared with a normal subject. The ability to excrete morphine residues has been increased about 20 %. However, the increase in the ability to excrete morphine residues in the urine accounts for 8 times as much of the increased ability of the addict to handle morphine, as does the increased ability to oxidize the methyl group of morphine. (Little can be said at present of the fate of the normorphine residue on loss of the methyl group. There also faintly remains the possibility that transmethylation between the N-methyl of morphine and some methyl donor such as choline may be involved, and that a conversion of morphine to normorphine or other nor-residue may not occur.)... 

The S-adenosyl homocysteine produced in the transmethylation reactions is generally cleaved to adenosine and homocysteine. The latter can be degraded as previously discussed or be remethylated to methionine and eventually regenerate S-adenosyl methionine. Thus the operation of a methionine cycle provides a route whereby one-carbon metabolites reduced through the tetrahydrofolic acid sequence provide methyl groups for biosynthetic pathways. Certain other sulphonium compounds such as... 

Later experimental work provided evidence that the 8-carbon polyketoacid intermediate in the synthesis of y-coniceine is derived from octanoic acid since this acid was shown to be readily incorporated into coniine. Further work indicated that 5-keto-octanoic acid and 5-keto-octanal were produced during the biosynthesis of y-coniceine. A transaminase (L-alanine 5-keto-octanal aminotransferase) was obtained from C. maculatum. This transaminase catalyzes the reaction between 5-keto-octanal with L-alanine as the amino group donor to form the piperidine ring and the propyl side chain. Another C. maculatum alkaloid, A-methylconiine, was shown to be produced by another enzyme from the plant a coniine methyltransferase which acts as a transmethylator utilizing 5-adenosyl-L-methionine as a methyl group donor. 

Transmethylation. Methionine is formed from homocysteine by the addition of a one-carbon moiety that becomes the methyl group of the thioether (VI). The methyl group of methionine may be derived from certain preformed methyl groups or from various one-carbon donors, such as serine and formate. In the latter case the one-carbon unit must... 

Adenosyl-L-methionine (SAM) was discovered in 1952 by Cantoni (1952), and its lUPAC name was designated as (25)-2-Amino-4-[[(25,35,4/ ,5/ )-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl-methylsulfonio] butanoate. The molecular structure in Fig. 16.1 shows that SAM possesses a sulfonium ion with a high group transfer potential. Thus each of the attached carbons is activated toward nucleophilic attack. SAM is involved in three types of important biochemical reactions within living cells, including transmethylation, transsulfu-ration, and aminopropylation. 

Demethylation of poly(sulfonium cation) occurs by nucleophile substitution reaction via Sn2 mechanism The demethylation is also classified as a transmethylation to nucleophiles. Using nucleophiles that have a mobile proton such as phenol, aniline and benzoic acid derivatives in the presence of potassium carbonate, demediyladon of poly( sulfonium cation) proceeds efficiently to yield the methylated products of phenol and benzoic acid with 100 % conversion (Scheme 2). In the case of aniline, both N-methyl and M -dimethyl aniline are obtained and methylation of -methyl aniline occurs more easily than aniline because of the higher Lewis basicity. 

The results presented in the Table 1 are in quantitative agreement with the distribution of active carbon atoms in the molecule of labeled variotin as indicated above. It was concluded that the Cja-straight chain of the Cig-hydroxy acid moiety of variotin was synthesized from 6 units of acetic acid by head-to-tail condensations. The 13 -methyl radical at the C-6 position was introduced by transmethylation. 

Degradation of cycloheximide, produced in the presence of L-methionine-Me-i C, showed that 96% of the isotope incorporated was present in the two methyl groups (carbons 15 and 16) of the dimethylcyclohexanone nucleus. This radioactivity was evenly distributed between these two methyl groups (Fig. 1). Negligible amounts (2.9%) of radioactivity were detected in carbons 2 to 8. Thus it seemed probable that carbons 15 and 16 were derived by transmethylation from methionine. 

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