D-Amino acids in post-translational modified neuropeptides

D-amino acids have been detected in a variety of peptides synthesized by animal cells. These include opiate and antimicrobial peptides from amphibian skin, neuropeptides from snail ganglia, an hormone from crustaceous, and a constituent of spider venom. DNA cloning has shown that at those positions where a D-amino acid is found in the end product, a normal codon for the corresponding L-amino acid is present. This implies that the D-residue are formed from L-amino acid by a post-translational reaction. A prototype enzyme has been isolated from the venom of the funnel web spider. An unusual modification in Conus peptides is the post-translational conversion of an L to a D amino acid which has been found in the I-conotoxin superfamily [1]. A potential correlation between the identity of the gene superfamily to which the I-conotoxin belongs and the presence or absence of a D-amino acid in the primary sequence is observed. The great diversity of the I-conopeptide sequence provides a rare opportunity for defining parameters that may be important for this most stealthy of all post-translational modifications. The results indicate that neither the chemical nature of the side chain nor the precise vicinal sequence around the modified residue seem to be critical, but there may be favoured loci for isomerization to a D-amino acid. Here we report about homologues sequences of the native peptide conotoxin, which is agonist toward neurotensin receptors, having L-leucine on the third amino acid from the C-terminus and the isomer with D-leucine in the same position. The conformational analysis of both sequences provide important insight in order to identify the structures and conformational changes involved in the binding with neurotensin receptors.