Proline occupies a special role among those amino acids incorporated into peptides and proteins by the normal ribosomal pathways, since it is the only residue that leads to anN-alkyl amide bond. In peptide natural products that often have special biosynthetic pathways or unusual posttranslational modifications,N-methyl amino acids are common and may play a special role because of their conformational properties, including their proclivity forcis-transisomerism of the amide bond. Numerous peptides with important biological activities, such as cyclosporin and didemnin, containN-methyl amino acids.Cis-transisomerism of theN-alkyl amide bond involving the amino group can readily be observed (1 ) in the NMR of proline andN-methyl amino acid-containing peptides. In the case of angiotensin and thyroliberin (TRH) analogs, the quantity ofcis-isomer in aqueous solution was correlated (2 ) with the biological activity. This suggested that thecis-isomer might be the one bound to the receptor and responsible for the observed biological activity. Bairaktari et al. (3 ) have reported that the normal amide bond between an He and Lys residues in the linear peptide, bombolitin, has thecis-conformation when bound to phospholipid micelles. In protei0n crystal structures,cis-amide bond conformations are occasionally observed for the normal, nonalkylated amide bond. Acis-amide bond predisposes the peptide for a reverse turn, a so-called Type VI β-turn. Brandl and Deber (4 ) have proposed thatcis-transisomerism of proline residue might play a role in transduction of transmembrane proteins.
