Anthracyclines, commonly used chemotherapy drugs, are reduced by the enzyme Human Carbonyl Reductase (HCBR) into their alcohol metabolites, which lack cytotoxicity and possess cardiotoxic properties. Understanding how HCBR recognizes and binds small molecules such as anthracyclines promises to provide insight into the design of non-substrate anthracyclines, or inhibitors that could be coadministered with the anthracyclines. A novel substrate, 2-acetyl-1-tetralone, was identified. Steady-state kinetic measurements estimated values of 2.5±0.5s-1, 220±20μM, and 0.011±0.002μM -1s-1 for kcat, Km, and kcat/Km values, respectively. Substrate inhibition was observed for concentrations above 400mM, and its kinetic properties were similar to that of the anthracycline Daunorubicin, suggesting its regioselective reduction by HCBR. Molecular modeling experiments led to the identification of a novel inhibitor candidate and to the hypothesis that the Met234 residue plays a role in anthracycline substrate specificity. The rate observed for 2-acetyl-1-tetralone compared to known substrates was anticipated by other molecular modeling experiment results.

Human carbonyl reductase as target for alleviating anthracycline cardiotoxicity: Understanding small molecule binding by human carbonyl reductase

249th National Meeting (2015)

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