Introduction

Abstract

Abstract During the past decade there has been an enormous increase in our understanding of the structure-function relationships and molecular mechanism of action of many of the toxins that affect protein synthesis. The toxins considered in this section inhibit eukaryotic cellular protein synthesis either by the NAO+ dependent adenosine diphosphate ribosylation of elongation factor 2 or function as an N-glycosidase to remove adenine 4324 (A4324) from 28S rRNA which leads to an impaired ability of the ribosome to bind elongation factors. The X-ray crystal structure of ricin (Montfort et al. 1987; Rutenber et al. 1991), Pseudomonas exotoxin A (Allured et al. 1986), diphtheria toxin (Choe et al. 1992; Bennett et al. 1994), and Shiga toxin (Fraser et al. 1994) have been solved. Both crystallographic and biochemical genetic analysis have led to a detailed understanding of the adenosine diphosphate ribosyltransferase activity of diphtheria toxin and Pseudomonas exotoxin A (Collier 1990; Wick and lglewski 1990) and the N-glycosidase activity of ricin, Shiga toxin, and the plant derived ribosome-inactivating proteins (Jimenez and Vasquez 1985; Stirpe and Barbieri 1986). Most all of these toxins have been highly purified, and their respective genes have been cloned and sequenced. In addition, many of their respective enzymatically active fragments or chains have been employed in the assembly of immunotoxins by the chemical crosslinking of the catalytic domains of either a bacterial or plant toxin to a monoclonal antibody (Ghetie and Vitetta 1994). More recently, recombinant DNA and protein engineering methods have been used to create chimeric genes in which the native receptor binding domain of either diphtheria toxin or Pseudomonas exotoxin A have been genetically substituted with one of a variety of genes encoding a polypeptide ligand that is directed toward a specific cell surface receptor or antigenic determinant on the target cell surface (for reviews see Kreitman and Pastan 1994; Murphy et al. 1995).