Abstract
Exogenous addition of methylthioadenosine (MeSAdo) inhibits proliferation of cells which are deficient in MeSAdo phosphorylase. A series of evidences has shown that the target of toxic mechanism of MeSAdo is not totally dependent on polyamine synthesis. Eukaryotic cells contain unique modified amino acid in elongation factor 2 (EF-2), designated as diphthamide. This residue is the specific target of mono(ADP-ribosyl)ation catalyzed by diphtheria toxin (DT) or Pseudomonous toxin. The structure of diphthamide is 2- [ 3-carboxyamido-3-(trimethylammonio)propyl]histidine, and the first reaction to modify histidine involves the transfer of an aminocarboxypropyl group from S-adenosylmethionine. MeSAdo should be the nucleoside product of this reaction. By these reasons, we have analyzed the effect of MeSAdo on the biosynthesis of diphthamide. A mutant cell line H3 which is deficient in MeSAdo phosphorylase and resistant to MeSAdo, has been isolated from murine lymphoma cell line R1.1. for the study. As measured by susceptibility to DT induced ADP-ribosylation, MeSAdo inhibits the formation of diphthamide in a dose dependent manner. In addition, MeSAdo substantially protected H3 cells from the lethal effect of DT. These results suggest that the modulation of diphthamide synthesis can be, at least a part of, the mechanism of MeSAdo toxicity toward eukaryotic cells.
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Yamanaka, H., Carson, D. 180 MODULATION OF DIPHTHAMIDE SYNTHESIS BY METHYLTHIOADENOSINE. Pediatr Res 24, 141 (1988). https://doi.org/10.1203/00006450-198807000-00204
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DOI: https://doi.org/10.1203/00006450-198807000-00204