Methionine, S-adenosylmethionine

Cysteine Methionine S-Adenosylmethionine synthase a-Methyltransferase S-Adenosylhomocysteinase Cystathionine- /3-synthase Cystathionine- y- lyase... 

Carnitine is synthesized from two essential amino acids, lysine and methionine. S-Adenosylmethionine donates three methyl groups to a lysyl residue of a protein with the formation of a protein-bound trimethyllysyl. Proteolysis yields trimethyllysine, which is converted to carnitine (Figure 18-2). In humans, liver and kidney are major sites of carnitine production from there it is transported to skeletal and cardiac muscle, where it cannot be synthesized. 

See also Methionine, S-Adenosylmethionine and Biological Methylations, Amino Acids Not In Proteins... 

The major biosynthetic pathway of ethylene in higher plants includes L-methionine, S-adenosylmethionine (AdoMet) and 1-anunocyclopropane-l-carboxylic acid (ACC) as the intermediates, and this pathway is commonly called the ACC pathway. It took a decade of extensive studies since methionine was confirmed as the precursor of ethylene in high plant tissues [24,25]. Before ACC was recognised as a direct precursor of ethylene [26,27]. However, some lower plants such as the semiaquatic fern Regnellidium diphyllum and the liverwort Riella helicophylla do not use ACC as a precursor, and there is convincing evidence for the presence of a non-ACC pathway [5]. However, the biochemical characterisation of this non-ACC pathway is yet to be performed. 

A naturally occuning sulfonium salt, S-adenosylmethionine (SAM), is a key substance in certain biological processes. It is fonned by a nucleophilic substitution in which the sulfur atom of methionine attacks the primary car bon of adenosine triphosphate, displacing the triphosphate leaving group as shown in Figure 16.7. 

FIGURE 16.7 Nucleophilic substitution at the primary carbon of adenosine triphosphate (ATP) by the sulfur atom of methionine yields S-adenosylmethionine (SAM). The reaction is catalyzed by an enzyme. 

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. 

The most common example of this process in living organisms is the reaction of the amino acid methionine with adenosine triphosphate (ATP Section 5.8) to give S-adenosylmethionine. The reaction is somewhat unusual in that the biological leaving group in this SN2 process is the triphosphate ion rather than the more frequently seen rliphosphate ion (Section 11.6). 

Adenosine triphosphate, coupled reactions and. 1128-1129 function of, 157, 1127-1128 reaction with glucose, 1129 structure of, 157, 1044 S-Adenosylmethionine, from methionine, 669 function of, 382-383 stereochemistry of, 315 structure of, 1045 Adipic acid, structure of, 753 ADP, sec Adenosine diphosphate Adrenaline, biosynthesis of, 382-383 molecular model of, 323 slructure of, 24... 

S-(5 -Deoxyadenosin-5 -yl)-L-methionine (AdoMet) S-[(1-Adenin-9-yl)-1,5-dideoxy-p-D-ribofuranos-5-yl]-L-methionine [trivial name S-adenosylmethionine (SAM)]... 

Figure 30-17. Formation of S-adenosylmethionine. -CHj represents the high group transfer potential of "active methionine."...

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 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... 

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... 

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

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. 

This enzyme [EC 2.1.1.10] catalyzes the reaction of S-adenosylmethionine with homocysteine to produce S-adenosylhomocysteine and methionine. With the bacterial enzyme, -methyhnethionine is a better substrate than 5-adenosyhnethionine. 

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. 

However, vitamin B12 also plays a role in the conversion of methionine to S-adenosylmethionine which could explain the neuropathy that results from vitamin B12 deficiency. 

Loehrer FMT, Haefeli WE, Angst CP, Browne G, Frick G, Fowler (1996) Effect of methionine loading on 5-methyltetrahydrofolate, S-adenosylmethionine and S-adenosylhomocyste-ine in plasma of healthy humans. Clin Sci 981 79-86... 

The formation of this complex cofactor occurs in one of only two known reactions in which triphosphate is cleaved from ATP (Fig. 3) the other reaction is the formation of S-adenosylmethionine from ATP and methionine (see Fig. 18-18). 

FIGURE 18-18 Synthesis of methionine and S-adenosylmethionine in an activated-methyl cycle. The steps are described in the text. In... 

Phosphocreatine, derived from creatine, is an important energy buffer in skeletal muscle (see Fig. 13-5). Creatine is synthesized from glycine and arginine (Fig. 22-26) methionine, in the form of S-adenosylmethionine, acts as methyl group donor. 

Methionine is one of four amino acids that form succinyl CoA. This sulfur-containing amino acid deserves special attention because it is converted to S-adenosylmethionine (SAM), the major methyl-group donor in one-carbon metabolism (Figure 20.8). Methionine is also the source of homocysteine—a metabolite associated with atherosclerotic vascular disease. 

Neurologic problems are common. The disease S-Adenosylmethionine t Methionine... 

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