Mode of Action of Diphtheria Toxin
نویسندگان
چکیده
In a preceding paper it was shown that low concentrations of diphtheria toxin, in the presence of NAD 1 as an essential cofactor, inhibit the incorporation of amino acids into TCA-precipitable peptides in mammalian cell extracts (1). Collier (2) has demonstrated that this inhibitory action of the toxin is due to the specific inactivation of transferase II , one of the highly labile soluble enzymes involved in transfer of amino acids from aminoacyl=tRNA to the growing peptide chain on the ribosome (3, 4). Goor and Pappenheimer (5) also concluded that transferase I I was the site of toxin action and provided evidence that soluble transferase I I was the only factor needed for protein synthesis that is lacking in extracts from intoxicated cells. I t was further concluded from quantitative studies (6) that toxin and transferase I I interacted stoicbeiometrically in the presence of NAD to form an inactive toxin-transferase I I complex. Although the model involving toxin-transferase I I complex formation proposed by Goor et al. (6) appeared to account for most of the quantitative relationships between toxin, NAD, and inhibition of peptide bond formation in cell-free extracts, it failed to explain how a mere 25-50 toxin molecules located in the outer cell membrane (7) could completely block protein synthesis and inactivate all of the soluble transferase I I in the living cell within a relatively short period of time. Moreover, the model failed to provide a satisfactory explanation for the striking reactivation of previously intoxicated cell extracts upon addition of nicotinamide (6). Finally, despite repeated efforts, we have been unable to obtain any direct evidence for the postulated toxin-NAD-transferase I I complex using either l*~I-labeled toxin or 14C-labeled NAD.
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