This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The polyamines putrescine, spermidine and spermine are important for cell growth and differentiation and are found in all forms of life. Elevated levels of the polyamines are found in rapidly proliferating cancerous and tumor cells and regulating the polyamine biosynthetic and the catabolic machinery is a promising tool for cancer therapy. S-Adenosylmethionine Decarboxylase (AdoMetDC) is a pyruvyl dependent decarboxylase and a critical enzyme in the polyamine biosynthetic pathway. The inhibitors to this enzyme have the potential to be anti-cancer drugs. AdoMetDC catalyses the conversion of S-Adenosylmethionine (AdoMet) to decarboxylated S-Adenosylmethionine (dcAdoMet) and the propylamine group of dcAdoMet is transferred to putrescine and spermidine to form spermidine and spermine respectively. Once decarboxylated, dcAdoMet is committed to the polyamine pathway. The primary goal of the project is to obtain crystal structures of AdoMetDC and key mutants with new inhibitors to determine their binding conformations and the key interactions they make to the enzyme. The structural information will help in the design of inhibitors which make favourable interactions with the enzyme and hence be more potent inhibitors of AdoMetDC.
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