CANCER PRODRUG ACTIVATING ENZYMES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NADPH-dependent FMN-reductase is an enzyme that is critical for electron transfer in all living organisms. These enzymes accept electron(s) from NADPH and transfers to substrates such as metal ions and organic compounds like quinones. Reduction of quinone based cancer prodrugs into active hydroquinones has been achieved by these enzymes. We have demonstrated already that the E. Coli FMN-reductase is very effective in cancer prodrug reduction and we are modifing this enzyme to enhance the catalytic activity. This enzyme will be a potential target for cancer prodrug therapy through nanoparticle drug delivery mechanism. This proposal is aimed at determining the wild-type crystal structure and explain the mechanism of the enzyme activity. We propose a hypothesis to optimize the enzymatic activity on the basis of crystal structure and would confirm by studying suitable mutants and protein-drug complexes.