Methionine transmethylation

STUDIES WITH DEUTERIUM The Biosynthesis of Methionine Transmethylation... 

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. 

Kauss, H., Swanson, A.L., and Hassid, W.Z. (1967) Biosynthesis of the methyl ester groups of pectin by transmethylation from S-adenosyl-L-methionine. Biochem.BiophysJies.Commun. 26 234-240. 

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. 

The transmethylation hypothesis depended on the psychosis of mescaline as an example of how methylated compounds similar in structure to the monoamine neurotransmitters could be psychotogenic, and demonstrated how methionine, the precursor of the methyl donor S-adenosylmethionine, could exacerbate the psychotic symptoms of schizophrenia in patients. This theory was fed by studies of the now notorious pink spot, an amine found in paper chromatography of urine extracts from schizophrenics and thought to be 3,4-dimethoxyphenylethylamine (i.e., O-methylated dopamine). Subsequent studies eventually identified this as another compound or compounds, primarily of dietary origin. Another methylated derivative erroneously proposed to be found in higher quantities in schizophrenia was dimethyltryptamine. This compound is similar in structure to LSD, the hallucinogenic nature of which was the key to the serotonin deficiency hypothesis, which proposed that the known antagonism of serotonin (5-HT) by LSD indicated that psychotic disorders such as schizophrenia may result from a hypofunction of 5-HT. 

The product of transmethylation, S-adenosylhomocysteine, is converted (step g) into homocysteine in an unusual NAD-dependent hydrolytic reaction (Eq. 15-14) by which adenosine is removed (step g).302c Homocysteine can be reconverted to methionine, as indicated by the dashed line in Fig. 24-16. This can be accomplished by the vitamin B12-and tetrahydrofolate-dependent methionine synthase, (Eq. 16-43), which transfers a methyl group from methyl-tetrahydrofolate303 303b by transfer of a methyl group from betaine, a trimethylated glycine (Eq. 24-33)304, or by remethylation with AdoMet (Fig. 24-16).304a... 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

S. K. Shapiro and F. Schlenck, eds., Transmethylation and Methionine Biosynthesis. Univ. of Chicago Press, Chicago, Illinois, 1965. 

Choline participates m normal fat metabolism and interrelates with methionine in a biochemical manipulation referred to as transmethylation. Choline, when in adequate quantity, cun replace the essential amino acid methionine when the latter is in limited quantity nr the reverse may wear, that is. methionine can be dismantled to replace choline. Choline delicienctes result in numerous degradalive physiologic changes in livestock. The usual dietary supplements are choline biianrale and choline chloride. 

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. 

Methyl Group as a Biologic Mark The Methyl Donor S-Adenosyl-I-Methionine Nucleophilic Methyl Groups Acceptors Spatial Control in Enzymatic Transmethylations Practical Implications... 

Methionine, homocysteine, and cysteine are linked by the methylation cycle and transsulfuratlon pathway (Figure 55-9). Conversion of methionine into homocysteine proceeds via the formation of S-adenosyl intermediates including S-adenosylmethionine, die methyl group donor in a wide range of transmethylation reactions. Homocysteine is further condensed with serine by cystathionine 3-synthase to form cystathionine. 

CAS 62-49-7. (CH3)3N(OH)CH2CH2OH. Member of the vitamin B complex. Essential in the diet of rats, rabbits, chickens, and dogs. In humans it is required for lecithin formation and can replace methionine in the diet. There is no evidence of disease in humans caused by choline deficiency. It is a dietary factor important in furnishing free methyl groups for transmethylation has a lipotropic function. 

Anderson et al. (103) carried out feeding experiments with cell cultures of A. altissima and L-[/Me7Ay/e/je- C]methionine and obtained radioactive 14. They supposed, therefore, that L-methionine would become S-adenosylmethionine and associate with transmethylation of 10 to produce 11. In accordance with growth of the cell culture, radioactive 11 gradually increases hence, they stated that the O-methyltransferase acts at the last stage of synthesis. 

The relation of many of the simpler alkaloids to the aromatic amino acids is obvious. For example, germinating barley contains (241), besides tyrosine and tyramine, A -methyltyramine, JViV -dimethyltyramine (hordenine), and the trimethylammonium derivative (candicine). In this simple case the. AT-methylated derivatives are known to be derivable from isotopically labeled tyramine (538) and the methyl groups are known to arise from methionine by transmethylation (540, 586). Similarly AT-methyl derivatives of phenylethylamine, 3,4-dihydroxyphenylethylamine, and 3,4,5-trihy-droxyphenylethylamine are well known alkaloids (cf. review, 701). N-Methylated derivatives of tryptamine and hydroxytryptamine equally occur for example, eserine has an obvious relation to 5-hydroxy tryptamine. Methylated derivatives of metabolites of the aromatic amino acids also occur, for example, trigonelline (67), which is the betaine of nicotinic acid, and damascenine is probably similarly related to hydroxyanthranilic acid. 

This essential amino acid contains an R-group with a methyl group attached to sulfur. Methionine serves as donor of a methyl group in many transmethylation reactions, e.g., in the synthesis of epinephrine, creatine, and... 

S-Adenosyl-L-methionine is the important methyl donor in biological transmethylation to form S-adenosyl-L-homocysteine, which is hydrolyzed to adenosine and homocysteine by S-adenosyl-L-homocysteine hydrolase (E.C. 3.3.1.1) in vivo. However, equilibrium of the S-adenosyl-L-homocysteine hydrolase reaction favors the direction toward synthesis of S-adenosyl-L-homocysteine. Shimizu et al. developed a simple and efficient method for the high yield preparation of S-adenosyl-L-homocysteine with S-adenosyl-L-homocysteine hydrolase of Alcaligenes faecalis, in which the cellular content of S-adenosyl-L-homocysteine hydrolase was about 2.5% of the total soluble protein. S-Adenosyl-r-homocysteine was produced at a concentration of about 80 g I. 1 with a yield of nearly 100% 661. However, when racemic... 

The biogenesis of nicotine has been studied in the plant with the aid of radioactive tracers. It was first shown that sodium formate is a precursor of the iV-methyl group of nicotine, but that methionine is a more immediate precursor since when these substances labeled with C are fed to the plant, the yield in radioactivity is greater with methionine than with formate (44). It was concluded that the methy-lation by methionine involved a true transmethylation and that the methyl group was not transferred via an intermediate oxidation to formate (44). This view found support in the results of an experiment involving the use of methionine with its methyl group doubly labeled with and deuterium. In this experiment, the ratio of the and... 

Newer data suggest that the primary antifungal action of edifenphos is due to interference of phosphatidylcholine biosynthesis by the transmethylation reaction of S-adenosyl-L-methionine. Therefore, the mode of action of edifenphos has a strong resemblance to that of IBP (Kitantin P ) (Kodama et al., 1980). 

Procarbazine may inhibit transmethylation of methyl groups of methionine into tRNA. The absence of functional tRNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the autooxidation of the drug, may attack protein sulfhydryl groups contained in residual protein that is tightly bound to DNA. 

S-Adenosylmethionine (AdoMet) is a metabolically activated form of methionine capable of donating a methyl group. AdoMet is formed in the reaction shown here. Transfer of a methyl group from AdoMet to a target molecule converts AdoMet to S-Adenosylhomocysteine (AdoHcy) (see here). Table 21.1 lists some important AdoMet-dependent transmethylations. Substrates range from small metabolites, such as norepinephrine, to polymers, such as DNA (see here), RNA, or proteins. 

For human beings methionine is nutritionally essential and comes entirely from the diet. ITowever, the oxoacid analog of methionine can be used as a nutritional supplement. Dietary homocysteine can also be converted into methionine to a limited extent. Methionine is incorporated into proteins as such and as N-formylmethionine at the N-terminal ends of bacferial profeins (steps a and b, Fig. 24-16). In addition to its function in proteins methionine plays a major role in biological methylation reactions in all organisms. It is converted into S-adenosylmethionine (AdoMet or SAM Fig. 24-16, step e see also Eq. 17-37), ° ° which is the most widely used methyl group donor for numerous biological methylation reactions (Eq. 12-3). S-Adenosylmethionine is also the precursor of the special "wobble base" queuine (Fig. 5-33). The product of transmethylation, S-adenosylhomocysteine, is converted (step... 

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