O

strate mimetic that directs the intrinsic synthesis activity of the protease to the side-chain carboxyl moiety of Asp and Glu (Scheme 5.1.4). Similar to linear substrate mimetics, the iso-type counterparts bear a site-specific ester leaving group which is, however, linked to the w-carboxyl moiety of Asp and Glu instead of being at the C-terminus of the peptide donor. This different architecture leads to a shift in the synthetic activity of the enzyme to the side-chain of Asp and Glu; this finally results in the formation of isopeptides.

More efficient than other methods, substrate mimetics enable proteases to react not only with non-specific coded amino acids, but also with non-amino acid-derived acyl donors. By using OGp esters of 4-phenylbutyric acid (Pbu-OGp) and benzoic acid (Bz-OGp) as the donor, a variety of amino acid amides and peptides as acyl acceptors, and clostripain and chymotrypsin as the catalysts the appropriate isosteric peptide products could be obtained in excellent yields [8, 12]. By using the unique specificity of clostripain toward the amino component the approach could even be expanded to the synthesis of a wide variety of N-linked neo-peptidoglycans. The approach enables selective coupling of carboxylate moieties derived from the side chains of Asp, Glu, and the C-terminus of peptides both with simple monomeric and with highly complex carbohydrates, for example D-glucosamine, d-galactosamine, muramic acid, and moenomycin A (Scheme 5.1.5) [13]. Even C-N bonds completely outside peptidic structures have been synthetic targets of the approach. For example, non-amino acid-derived carboxylic components, for example Pbu-OGp and Bz-OGp, and a large number of non-peptidic amino components, for example aliphatic and aromatic amines, amino alcohols, non-a-amino carboxylic acids, and diamines, have been efficiently coupled [12]. To conclude, this remarkable activity opens up new possibilities of easy synthesis of a broad spectrum of linear peptides, isopeptides, all-D peptides, peptide isosteres, peptide-carbohydrate conjugates, and non-amino acid-derived carboxylic acid amides under extraordinary mild conditions unachievable with classical protease approaches.

Scheme 5.1.5. Clostripain-mediated coupling of the Leu-enkephalin sequence Z-Asp-Tyr-Gly-Gly-Phe-Leu-OH with a moenomycin A analog.

396 | 5.1 Protease-catalyzed Formation of C-N Bonds 5.1.5

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