Biogenesis of D-amino acid containing peptides/proteins: where, when and how?

Peptides and proteins are chiral molecules with their structure determined by the composition and configuration of the amino acids constituting them. Natural amino acids (except glycine) display two chiral types (L-and D-enantiomers). For example, the presence of octopine, a derivative of L-arginine and D-alanine in octopus, or peptidyl poly-D-glutamic acid in a bacterial cell wall was demonstrated in the 1920s and 1930s, respectively. Nevertheless, an old dogma in biology was that proteins (in a strict sense) are composed of amino acids in the L-configuration exclusively, until a D-alanyl residue was reported in a frog skin opioid peptide in the early 1980s, and since, numerous D-amino acid containing peptides (DAACPs) have been discovered in multicellular organisms. Several hypotheses may be formulated to explain the origin of a D-residue in the peptide/protein chain. It may result from different mechanisms such as incorporation of a D-amino acid, non-enzymatic racemisation associated with ageing or diseases and enzymatic posttranslational modification. In the last case, the DAACPs are synthesised via a ribosome-dependent manner, and a normal codon for L-amino acid is present in the mRNA at the position where the D-residue is processed in the mature peptide by peptidyl aminoacyl L-D isomerisation, a peculiar and subtle posttranslational modification. In this review, the different pathways of biogenesis of DAACPs not only in bacteria but also in multicellular organisms are discussed, along with the description of the cellular specificity, the enzyme specificity and the substrate specificity of peptidyl aminoacyl L-D isomerisation. Copyright (C) 2014 European Peptide Society and John Wiley & Sons, Ltd.