Tryptophan 2-thioether

The major metal-binding amino acid side chains in proteins (Gurd and Wilcox, 1956 see Voet and Voet, 1990) (Table II) are carboxyl (aspartic acid and glutamic acid), imidazole (histidine), indole (tryptophan), thiol (cysteine), thioether (methionine), hydroxyl (serine, threonine, and tyrosine), and possibly amide groups (asparagine and glutamine, although... 

In summary, protein molecules may contain up to nine amino acids that are readily derivatizable at their side chains aspartic acid, glutamic acid, lysine, arginine, cysteine, histidine, tyrosine, methionine, and tryptophan. These nine residues contain eight principal functional groups with sufficient reactivity for modification reactions primary amines, carboxylates, sulfhydryls (or disulfides), thioethers, imidazolyls, gua-nidinyl groups, and phenolic and indolyl rings. All of these side chain functional groups in addition to the N-terminal a-amino and the C-terminal a-carboxylate form the full complement of polypeptide reactivity within proteins (Fig. 12). 

FIGURE 14.4 The Cu ligands of galactose oxidase (Tyr 272, Tyr 495, His 496 and His 581), the Cys228 which forms the thioether bond to Tyr 272, the tryptophan that stacks over it (Trp 290) and Phe 227. (From Rogers Dooley, 2003. Copyright 2003, with permission from... 

The tyrosyl radical is bound to Cys 228 via a thioether. It is as yet unclear how this bond is formed it may possibly arise during the first catalytic cycle of the enzyme. It is improbable that the bond is formed by another enzyme as the thioether is concealed beneath tryptophane 290 and is, therefore, inaccessible to... 

Oxidative degradative reactions can occur to the side chains of sulfur-containing methionine (Met) and cysteine (Cys) residues and the aromatic amino acid residues histidine (His), tryptophan (Trp), and tyrosine (Tyr) in proteins during their isolation and storage. The weakly nucleophilic thioether group of Met (R-S-CH3) can be oxidized at low pH by hydrogen peroxide as well as by oxygen in the air to the sulfoxide (R-SO-CH3) and the sulfone (R-SO2-CH3). The thiol... 

On hydrolysis with acids phalloidin yields L-alanine, 4-cis-L-hydroxyproline, D-threonine, L-y, -dihydroxyleucine, L-cysteine and j8-oxindolalanine ( oxytryptophan ). The tryptophan derivative is not a genuine building component of the cyclic peptides it is formed by hydrolysis of a thioether crosslink between position 2 of tryptophan and the side chain of cysteine (tryptathionine). The structure of the bicyclic heptapeptide is shown in Fig. 21. 

To generate the thioether bridge a suitable cysteine containing tetrapeptide was linked via the S-chloride to the indole ring of a tryptophan containing tripeptide that carried the lactone of y-hydroxyleucine at its C-terminus. A shown in Fig. 22, the first cyclization led to the secolactone which, after the... 

Electrophilic substitution of aromatic nuclei in tyrosine and tryptophan side chains has frequently been reported in connection with acidolytic removal of blocking groups. C-Benzylation and tert.butylation of the tyrosine side chain and N-alkylation of the indole nucleus in tryptophan are often attributed to the alkyl cations generated in the reaction. This common side reaction is caused, however, mainly by the alkylating agents formed in the process, such as benzyl bromide or tert.butyl trifluoroacetate. The same is true for the S-alkylation of the methionine side chain. Conversion of the thioether to a sulfonium salt can... 

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. 

These reactions which lead to homocysteine formation in some creatures and its utilization in others are undoubtedly representative of a general thiol group transfer mechanism. The initial condensation of the donor thiol, most commonly cysteine, with some suitably reactive receptor generates a thioether. The differences in the requirement for O-acylation when starting from serine and homoserine may refiect two completely different mechanisms for this thiol substitution reaction. In the case of serine, the removal of the hydroxyl as hydroxide and the stabilization of an electrophilic centre on the side-chain carbon can be achieved through the pyridoxal phosphate-amino acid adduct. A similar example is in the carbon-carbon condensation between serine and imidazole in tryptophan... 

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