Methionine sulfonium derivative

It is well known that sulfonium salts derived from methionine may decompose in many ways. Electron-withdrawing groups on the sulfur atom promote the breakdown of the sulfonium salt by bimolecular or intramolecular nucleophilic displacement. In the case of acetyl-methionine sulfonium derivatives (21) the displacement reaction takes place with the participation of the C-carbonyl group via a 1,5-interactipn, resulting in elimination of the dialkyl sulfide and formation of homoserine iminolactone (22) which on hydrolysis gives homoserine lactone (23) (reaction 17) . Best results are obtained when the reac-... 

A sulfonium derivative, abbreviated AdoMet or SAM, that is primarily generated by the action of methionine adenosyltransferase (ATP + L-methionine + H2O SAM + Pi + pyrophosphate). SAM is a major methylat-... 

The method described above gives direct analysis of methionine sulfoxide content in proteins. Another method makes use of carboxy-methylation of methionine at acid pH to give the carboxymethyl-sulfonium derivative ( 3.5). Methionine sulfoxide, which is not affected by the carboxymethylation reaction, is then oxidized to the sulfone which is stable to acid hydrolysis and can easily be quantitated. This is possible because methionine carboxymethyl-sulfonium salts are not affected by performic acid oxidation, although they are degraded by acid hydrolysis. Therefore, the methionine sulfone content is equal to the methionine sulfoxide content plus any sulfone that may have been initially present (shown by analysis before oxidation). 

This side reaction is relatively innocuous because the by-product is irreversibly bound to the polymer and only the yield is affected not the purity of the synthetic peptide. More disturbing is the succinimide ring formation at aspartyl residues exposed to HF. Alkylation of the indole ring in tryptophan, the phenolic side chain in tyrosine and the sulfur atom in methionine must be suppressed by the addition of scavengers. The often appUed anisole is less than unequivocal in this role it can be the source of methyl groups which convert the methionine thioether to a tertiary sulfonium derivative. The acid stable thioanisole seems to be a better scavenger. 

Adenosylmethionine is a sulfonium derivative of methionine and has a higher energy content than the parent methionine. The compound has been synthesized (75) and the synthetic product shown to participate in enzymic reactions to the extent expected (76). 

The action of cysteine desulfhydrase is inhibited by hydrogen cyanide. Binkley and du Vigneaud (15) have observed that the production of hydrogen sulfide, which appears in the comrse of the reaction due either to homocysteine desulfhydrase or to cysteine desulfhydrase, is arrested in the presence of hydrogen cyanide, without however diminishing appreciably the yield of cysteine. This observation shows that the mechanism in question does not come into play in the experiments of Binkley and du Vigneaud, but the re.sults do not show that this mechanism plays no role in the animal. The theory of Toennies (121) assumes the existence of a direct transsulfuration between methionine and serine. This theory is based on the ability of methionine sulfur to form sulfonium derivatives... 

The sulfur atom of methionine residues may be modified by formation of sulfonium salts or by oxidation to sulfoxides or the sulfone. The cyanosulfonium salt is not particularly useful for chemical modification studies because of the tendency for cyclization and chain cleavage (129). This fact, of course, makes it very useful in sequence work. Normally, the methionine residues of RNase can only be modified after denaturation of the protein, i.e., in acid pH, urea, detergents, etc. On treatment with iodoacetate or hydrogen peroxide, derivatives with more than one sulfonium or sulfoxide group did not form active enzymes on removal of the denaturing agent (130) [see, however, Jori et al. (131)]. There was an indication of some active monosubstituted derivatives (130, 132). 

With methyl iodide as the alkylating reagent, Link and Stark (133) prepared a monosubstituted sulfonium salt. Methionine 29 was strongly indicated as the principal site of modification. The activity of the derivative toward C>p was the same as RNase-A, and the methylation reaction was not affected by competitive inhibitors such as 2 (3 )-UMP. 

Methionine 13 in S-peptide has been modified by oxidation to the sul-fone or by conversion to a sulfonium salt with either iodoacetic acid or iodoacetamide (138). There is a dramatic lowering of the peptide-protein binding constant for all of the derivatives, but the complexes when formed appear to have nearly normal catalytic activity. The X-ray structure does not appear to permit the normal sulfur location with the sulfonium salts. Sterically, Met 13 can be moved by rotation about the carbon a-carbon / bond so that the residue sticks out into the solvent. This can be done without any major change in the conformation of the rest of the peptide. Thus the active site could be maintained undisturbed while the contribution of Met 13 to the S-peptide S-protein association would be lacking. 

The first metal(salen) complex investigated as an asymmetric phase-transfer catalyst was methionine-derived sulfonium salt 29. It was anticipated that the sulfonium salt... 

In view of these many precedents it is surprising that the intramolecular displacement of the sulfur function of methionine derivatives has not been utilized for selective cleavage of methionine peptides. The method has only recently been applied to a number of methionine peptides which according to the following scheme (CXX-CXXIII) were first converted to sulfonium salts and then subjected to intramolecular (imino) lactonization and hydrolysis by short heating in water (Lawson et al., 1961). Table XV shows the strong influence of the nature of the added alkyl group on the yield in... 

The derivatives of methionine formed by haloketones are not stable to the usual conditions of acid hydrolysis. These sulfonium salts are degraded in three different ways. Some methionine is regenerated, some homoserine and homoserine lactone is formed and possibly the homocysteine derivative of the general structure indicated below is produced where X represents the rest of the affinity label. 

Methionine is utilized primarily in protein synthesis, providing sulfur for cysteine synthesis, and is the body s principal methyl donor. In methylation reactions, S-adenosylmethionine (SAM) is the methyl group donor. SAM is a sulfonium compound whose adenosyl moiety is derived from ATP as follows ... 

Hi) Methionine Sulfoxide and Sulfone. Under controlled conditions, mild oxidizing agents convert methionine to its sulfoxide. It can also be formed by simple exposure of peptides and proteins to air for a long period of time. This derivative is unstable to acid and only partial recovery is observed after such treatment, but accurate estimates can be made from alkaline or enzymatic hydrolyses (Means and Feeney, 1971). It can also be determined by difference, a method which takes advantage of the fact that the sulfoxide does not react with alkylating agents and that sulfonium salts cannot be further oxidized to the sulfone (Neumann et a/., 1962). 

It should be noted that the sulfur atom in methionine sulfoxide is a new chiral center, hence a pair of diastereosimers is present in the intermediates. This is a minor complication that is absent from an alternative method for the masking of the thioether its more recently proposed conversion to a tert.sulfonium salt by the reaction of an activated N-acyl derivative of the amino acid with methyl p-toluenesulfonate ... 

L-Methionine, (S)- -amino-y-methylthiobutyric acid, is one of the most important sulfur-containing primary amino acids. Secondary products derived from L-methionine either contain still the more or less complete methionine skeleton [cf. the formulas of S-adenosyl-L-methionine, azetidine-2-carboxylic acid, 1-aminocyclopropane carboxylic acid (Fig. 192), spermidine and spermine (Fig. 193)], or only the methyl group of L-methionine (most 0-, iV-, S- and C-methylated secondary products). The sulfur-containing derivatives possess either a sulfide (—S—) or a sulfonium (—S+—) group. 

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