Diphtheria-related peptide hormone gene fusions: A molecular genetic approach to chimeric toxin development

Publisher Website
Google Scholar
Abstract
Over the past 15 years there has been a considerable increase in the level of understanding of the structural functional domains of the diphtheria toxin molecule (see Chapters 3 and 4). This understanding has led to the postulation that diphtherial intoxication of intact sensitive eukaryotic cells results from an ordered series of interactions between the toxin molecule and the cell. For example, the intoxication of a eukaryotic cell must involve at least the following steps: 1) the binding of toxin to its receptor on the cell surface, 2) internalization of toxin by receptor mediated endocytosis and, upon acidification of the endocytic vesicle, 3) a partial unfolding of fragment B, which leads to 4) the delivery of fragment A across the cell membrane and into the cytosol, and 5) the nicotinamide adenine dinucleotide (NAD)-dependent adenosine diphosphate (ADP)-ribosylation of eukaryotic elongation factor 2. Modified elongation factor 2 is unable to catalyze the translocation of polypeptidyl-tRNA from the aminoacyl (‘A’) to the polypeptidyl (‘P’) site on the ribosome, and therefore protein synthesis is inhibited. This series of steps results in diphtherial intoxication and ultimate death of the intact sensitive eukaryotic cell.