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- W1496011481 abstract "4483 As a rate limiting enzyme in the polyamine biosynthetic pathway, S-adenosylmethionine decarboxylase (AdoMetDC) is a target for potential therapeutic intervention against various cancers. In an effort to better understand the enzyme/substrate interactions at the active site of AdoMetDC, we have investigated the effects of several mutations of the amino acid glutamic acid at position 247 (E247). Crystal structures of AdoMetDC suggest that this residue interacts with the hydroxyl groups of the ribose moiety in the natural substrate S-adenosylmethionine (AdoMet). C-terminally his-tagged hAdoMetDC proteins with amino acids alanine (A), aspartic acid (D), or glutamine (Q) substituted at E247 were constructed and purified. Activity assays were then carried out with AdoMet substrate to determine the kinetic parameters of the mutant proteins relative to the wild-type hAdoMetDC. The results indicated that the E247Q mutation had no effect on Vmax, Km or kcat. However, both the E247A and E247D mutations significantly reduced the activity and caused a large increase in Km, as well as large decreases in Vmax and kcat. Since one of the goals of these studies is to design efficient inhibitors of AdoMetDC, we have investigated the ability of the classic inhibitor methylglyoxal bis(guanylhydrazone)(MGBG) to inhibit the activity of the E247 mutant proteins. Preliminary results from determinations of Ki values indicate that although the E247Q mutation has little effect on activity, it significantly alters the interaction with MGBG at the active site as the Ki value is significantly increased over that of the wt-hAdoMetDC. Not surprisingly, the Ki values for MGBG with the E247A and E247D mutants were also significantly increased relative to the wild-type protein. Additional known AdoMetDC inhibitors are currently under investigation. These results strongly suggest that the E247 residue of the AdoMetDC protein is important to the enzyme/substrate interaction at the active site and that this interaction should be preserved and/or exploited in design of AdoMetDC inhibitors. This work was supported by NIH grant CA 094000." @default.
- W1496011481 created "2016-06-24" @default.
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- W1496011481 date "2007-05-01" @default.
- W1496011481 modified "2023-09-23" @default.
- W1496011481 title "Effects of mutation at glutamic acid 247 on activity and kinetic parameters of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase." @default.
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