Lanthionine-forming reactions

A further approach for the synthesis of nonsymmetrically protected lanthionines is the conversion of thiosulfinates of symmetrically protected cystine derivatives into nonsymmetrically protected cystines via a reaction with a cysteine derivative and subsequently the conversion of the resulting unsymmetrically protected cystine into the nonsymmetrically protected lanthionines with a tris(dialkylamino)phosphineJ26l The oxidation of the symmetrically protected cystine, e.g. A,AT-bis(benzyloxycarbonyl)-L-cystine diethyl ester, of one stereochemical configuration to the thiosulfinate with m-chloroperoxybenzoic acid is essentially quantitative. The nonsymmetrical cystine is then formed in a subsequent step by the addition of the /V-/er/-butoxycarbonyl-L-cysteine tert-butyl ester derivative to give N-Z-N -Boc-L-cystine ethyl ferf-butyl diester. The desired 2f ,6f -lanthionine is then formed in the presence of P(NEt2)3 in yields of >50%. 

In contrast to the syntheses described above, which all start from cystine derivatives to form lanthionine, the lanthionine syntheses in this section all start from a protected cysteine as the nucleophilic precursor, which is then allowed to react with any of a variety of different substrates. These subsequent reactions are the Michael addition with dehydroalanine, the nucleophilic substitution of halo amino acids, or the ring-opening reaction of serine p-lactones and aziridines, respectively. However, it must be emphasized that the Michael... 

Effects of Alkali. Although alkali had been used to treat certain foods for many years, only recently has it been used widely by the texturized protein industry. Alkali-mediated degradation of proteins has long been known (13, 39-44). Some of the main initial reactions are apparently / -eliminations of cystines and substituted serines and threonines. The products (or their intermediates) then alkylate various other amino acid side chains to form substances like lanthionine and lysino-alanine [N -(DL-2-amino-2-carboxyethyl)-L-lysine]. Possible toxicities are currently under investigation (45, 46), but nutritional losses could also be important. 

Lysinoalanine is formed by -elimination reaction of cystine-cysteine and serine with the formation of dehydroalanine and the subsequent addition of the e-amino group of lysine across the reactive C—C double bond (30). The formation of other amino acids such as ornithinoalanine (31), lanthionine (32), and /3-aminoalanine (33) by similar mechanism has been described. Gross et al. (34) have pointed out that lysinoalanine... 

Two major chemical modifications of proteins that occur during alkaline treatment are crosslinking and racemlzation. Lysine, ornithine (via arginine), cystine and 0-substituted serine can participate in base-catalyzed reactions forming the crossllnked amino acids lysinoalanine, ornithinoalanine and lanthionine Under the same conditions, inversion can occur when the or hydrogen of an amino acid residue is abstracted by the base, resulting in a planar, optically inactive carbanion ( ), as illustrated in Figure 1. The carbanion may be reprotonated from either face of the plane, which causes inversion when this occurs from the opposite face. 

Formation of lanthionyl residues during alkaline treatment of keratin fibers was first suggested by Speakman [61] and later demonstrated by Horn et al. [62]. Lanthionyl residues may be formed from cystinyl residues in proteins under relatively mild alkaline conditions 35°C and pH 9 to 14 [42]. However, under these same reaction conditions, lanthionine has not been identified from free cystine. For that matter, thioethers have not been formed from organic disulfides other than cystine-containing proteins, using... 

The formation of lanthionine in keratin libers is believed to involve two reaction sequences. The first sequence consists of beta-elimination to form dehydroalanine residues in hair ... 

For wool fiber, all three residues—lanthionine, lysinoalanine, and beta-aminoalanine—have been shown to form from reactions under alkaline conditions [67,70,71], In the case of human hair, only lanthionine and lysinoalanine have been shown to form under alkaline conditions [68],... 

The lantibiotics differ extensively from the class II bacteriocins in that they contain post-translationally modified amino acids, as for example dehydrated amino acids and lanthionine residues, forming intramolecular thioether bridges [39, 184]. The chemical modification reactions leading to the typical lanthionines were first proposed by Ingram [185] and are assumed to be catalyzed by specific enzymes encoded in the lantibiotic gene cluster. In the lantibiotic lactocin S, p-alanine residues were discovered, probably by conversion of dehydrated serine residues via a dehydrogenation reaction [82]. In some... 

Cystine residues in wool are attacked by alkali [13,242], and two new cross-links lanthionine and lysinoalanine—are formed. A mechanism for the reaction of cystine residues with alkali has been suggested. 

The cited evidence for the B-elimination mechanism leading to dehydroalanine formation merits further comment. Nashef et al. (41) report that alkali-treatment of lysozyme ribonuclease and several other proteins resulted in loss of cystine and lysine residues and the appearance of new amino acids lysinoalanine, lanthionine, and B-aminoalanine. Alkali-treatment of the proteins induced an increase in absorbance at 241 nm, presumably from the formation of dehydroalanine residues. The dehydroalanine side chain can participate in nucleophilic addition reactions with the e-NH2 group of lysine to form lysinoalanine, with the SH groups of cysteine to form lanthionine, and with ammonia to form B-aminoalanine. 

Figure 12. Transformation of dehydroalanyl to lysinoalanine (LAL), S-B-(2-pyridylethyl)-L-cysteine (2-PEC), and lanthionine (LAN) residues in a protein. Hydroxide ions induce elimination reactions in cysteine and serine to form dehydroalanine. The double bond of dehydroalanine then interacts with the e-NH2 group of lysine to form LAL, with the SH group of cysteine to form LAN, and with the SH group of added 2-mercaptoethylpyridine to form 2-PEC. The latter is identical to the compound obtained from cysteine and 2-vinylpyridine.

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